Probes for imaging huntingtin protein

ABSTRACT

Provided are imaging agents comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and methods of their use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/249,223, filed Aug. 26, 2016, which claims the benefit under 35U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 62/211,118,filed on Aug. 28, 2015, each of which is hereby incorporated byreference in their entirety.

FIELD

The present disclosure relates to imaging agents that bind toabnormalities of the HTT protein with high sensitivity and specificityfor molecular imaging and methods of use of such imaging agents.

BACKGROUND

The advent of molecular imaging approaches such as positron emissiontomography (PET) and single photon emission computed tomography (SPECT)has enabled measurements of molecular and cellular mechanisms throughoutthe body in preclinical and clinical settings. Such measurements havewidespread diagnostic utility and their use for evaluation of treatmentresponses and to assist drug development is expanding rapidly. Therecent introduction of high-resolution molecular imaging technology isconsidered by many experts as a major breakthrough that will potentiallylead to a revolutionary paradigm shift in health care and revolutionizeclinical practice.

PET involves the administration to a subject of a positron-emittingradionuclide tracer followed by detection of the positron emission(annihilation) events in the body. The radionuclide tracer is typicallycomposed of a targeting molecule having incorporated therein one or moretypes of positron-emitting radionuclides.

Many new molecular probes labeled with positron-emitting radionuclidesand associated PET imaging assays are under development to target,detect, visualize, and quantify various extracellular and intracellularmolecules and processes associated with diseases such as cancer, heartdisease, and neurological disorders. For instance, several types ofagents have been synthesized and evaluated for imaging amyloid β (Aβ)plaques in patients with Alzheimer's disease (AD) including,arylbenzothiazoles, stilbenes, imidazopyridines, pyridylbenzothiazoles,pyridylbenzoxazoles and pyridylbenzofurans (Swahn et al., Bioorganic &Medicinal Chemistry Letters, 20 (2010) 1976-1980). Furthermore,styrylbenzimidazole (SBIM) derivatives have been developed as agents forimaging neurofibrillary tangles (NFT), composed of hyperphosphorylatedtau protein, in patients with AD. In binding experiments usingrecombinant tau and amyloid β₁₋₄₂ (Aβ₁₋₄₂) aggregates,4-[(E)-2-(6-iodo-1H-benzimidazol-2-yl)ethenyl]-N,N-dimethylaniline(SBIM-3) showed higher affinity for the tau aggregates than Aβ₁₋₄₂aggregates (ratio of K_(d) values was 2.73). In in vitro autoradiographyand fluorescent staining, [¹²⁵I]SBIM-3 (or SBIM-3) bound NFT in sectionsof AD brain tissue. In biodistribution experiments using normal mice,all [¹²⁵I]SBIM derivatives showed high initial uptake into (3.20-4.11%ID/g at 2 minutes after the injection) and rapid clearance from(0.12-0.33% ID/g at 60 minutes after the injection) the brain (Matsumuraet al., Bioorganic & Medicinal Chemistry, 21 (2013) 3356-3362).

Huntington's disease (HD) is an inherited progressive neurodegenerativedisorder, characterized by motor, cognitive, and psychiatric deficits aswell as neurodegeneration and brain atrophy beginning in the striatumand the cortex and extending to other subcortical brain regions. Itbelongs to a family of neurodegenerative diseases caused by mutations inwhich an expanded CAG repeat tract results in long stretches ofpolyglutamine (polyQ) in the encoded mutant protein. This family alsoincludes dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbarmuscular atrophy (SBMA) and the spinocerebellar ataxias (SCAs). Apartfrom their polyQ repeats, the proteins involved are unrelated, andalthough they are all widely expressed in the central nervous system andperipheral tissues, they lead to characteristic patterns ofneurodegeneration.

In HD, the selective neurodegeneration of the γ-aminobutyricacid-releasing spiny-projection neurons of the striatum is predominant,although loss of neurons in many other brain regions has also beenreported. In the unaffected population, the number of CAG repeats in theIT₁₅ gene that encodes the HD protein huntingtin (HTT protein) variesfrom 6 to 35. CAG repeats of 36 or more define an HD allele, therebyresulting in translation of a mutant huntingtin protein (mHTT)containing a longer polyQ stretch. This mHTT protein is prone tomisfolding and aggregate formation. The length of the CAG expansion isinversely correlated with age of disease onset, with cases of juvenileonset characterized by expansions of more than 60 repeats. HD has aprevalence of 5-10 cases per 100,000 worldwide, which makes it the mostcommon inherited neurodegenerative disorder.

The HTT protein is a 348-kDa multidomain protein that contains apolymorphic glutamine/proline-rich domain at its amino-terminus. Thelonger polyQ domain of mHTT seems to induce conformational changes inthe protein, which causes it to form intracellular aggregates that, inmost cases, manifest as nuclear inclusions. However, aggregates can alsoform outside of the nucleus. mHTT protein is present in the nucleus,cell body, dendrites and nerve terminals of neurons, and is alsoassociated with a number of organelles including the Golgi apparatus,endoplasmic reticulum and mitochondria.

Several clinical trials are investigating means to alleviate or reducesymptoms and slow progression in clinically diagnosed HD. Consistentwith other medical conditions, treatments might be ideally initiated ator before the earliest signs of disease. There are at least two primarychallenges to the design of clinical trials for pre-HD: selection ofparticipants who are most likely to show measurable change over thecourse of a clinical trial, and development of outcome measures that aresensitive to interventions and can demonstrate variation over thenatural history of pre-HD. In order to meet these and other challengesto preventive clinical trials, indicators of very early disease arerequired.

In view of the central role of the accumulation of aggregated forms ofHTT protein (i.e. mHTT) in the pathogenesis of HD, there is a need formolecular probes that bind to such abnormalities with high sensitivityand specificity for molecular imaging in the living subject using PET.The compounds described herein meet this and other needs.

SUMMARY

Provided is an imaging agent comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

m is 0, 1, or 2;

n is 1 or 2;

J is C(═O) or —CH—;

X is S or N;

Y is CH or N;

Z is CH or N;

W is N or S;

for each occurrence, R₁ is independently chosen from halo, lower alkoxy,hydroxy, aryl, heteroaryl, cycloalkoxy, or lower alkyl, wherein thelower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl are eachoptionally substituted with one, two, or three groups independentlyselected from lower alkoxy, alkenyl, —NR₄R₅, halo, or heteroaryloptionally substituted with one to three lower alkoxy;

R₂ is hydrogen or lower alkyl; and

R₃ is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, or heteroaralkyl, each of which is optionally substitutedwith one, two, or three groups independently chosen from hydroxy, loweralkoxy optionally substituted with lower alkoxy or halo, lower alkyloptionally substituted with halo, halo, heteroaryl, —(CH₂)NR₄R₅, oxo,cyano, or —C(O)—NR₄R₅, or

R₂ and R₃ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₄R₅;

t is 0, 1, or 2;

each R₄ is independently chosen from hydrogen or lower alkyl;

each R₅ is independently chosen from hydrogen or lower alkyl; or

R₄ and R₅ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₆R₇;

each R₆ is independently hydrogen or lower alkyl; and

each R₇ is independently hydrogen or lower alkyl;

wherein the compound of Formula I, or a pharmaceutically acceptable saltthereof, is labeled with one or more positron-emitting radionuclides.

Also provided is a method of generating diagnostic images in anindividual comprising administering an effective amount of an imagingagent described herein to an individual, and generating an image of atleast a part of said individual.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows that Aβ aggregates are visible in the 12-month oldheterozygous, APP/PS1 mouse brain after incubation with 1 nM10-[³H]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide.

FIG. 1B shows the binding of the same compound in wild type mouse brain.

FIG. 2 shows binding of the positive control compound ³H-PiB to 18-monthold heterozygous APP/PS1 mouse brain.

FIG. 3 shows AUC values for binding of10-[¹¹C]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamidein four regions of the brain in wild type mice and mice that areheterozygous or homozygous for the zQ175 knock-in allele.

FIG. 4A and FIG. 4B show mHTT aggregates are visible in the 10 week oldR6/2 mouse brain after incubation with 0.5 nM7-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]imidazo[2,1-b]thiazole-2-carboxamide(as shown in FIG. 4A) as compared with a wild-type littermate (as shownin FIG. 4B).

DETAILED DESCRIPTION

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

As used herein the terms “group”, “radical” or “fragment” refer to afunctional group or fragment of a molecule attachable to a bond or otherfragments of molecules.

When a range of values is given (e.g., C₁₋₆ alkyl), each value withinthe range as well as all intervening ranges are included. For example,“C₁₋₆ alkyl” includes C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₂₋₆, C₃₋₆, C₄₋₆,C₅₋₆, C₁₋₅, C₂₋₅, C₃₋₅, C₄₋₅, C₁₋₄, C₂₋₄, C₃₋₄, C₁₋₃, C₂₋₃, and C₁₋₂alkyl.

When a moiety is defined as being optionally substituted, it may besubstituted as itself or as part of another moiety. For example, if RXis defined as “C₁₋₆ alkyl or OC₁₋₆ alkyl, wherein C₁₋₆ alkyl isoptionally substituted with halogen”, then both the C₁₋₆ alkyl groupalone and the C₁₋₆ alkyl that makes up part of the OC₁₋₆ alkyl group maybe substituted with halogen.

The term “alkyl” encompasses straight chain and branched chain havingthe indicated number of carbon atoms, usually from 1 to 20 carbon atoms,for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. Forexample C1-C6 alkyl encompasses both straight and branched chain alkylof from 1 to 6 carbon atoms. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl,and the like. When an alkyl residue having a specific number of carbonsis named, all geometric isomers having that number of carbons areintended to be encompassed; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, isobutyl and tert-butyl; “propyl” includesn-propyl and isopropyl. “Lower alkyl” refers to alkyl groups having 1 to6 carbons.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refersto alkoxy groups having 1 to 6 carbons. By “cycloalkoxy” is meant acycloalkyl group that is likewise attached through an oxygen bridge.

“Alkenyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to6 carbon atoms) and at least one carbon-carbon double bond derived bythe removal of one molecule of hydrogen from adjacent carbon atoms ofthe corresponding alkyl. Alkenyl groups include, but are not limited to,ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-2-en-1-yl) and butenyl(e.g., but-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl). “Lower alkenyl”refers to alkenyl groups having 2 to 6 carbons.

“Alkynyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to6 carbon atoms) and at least one carbon-carbon triple bond derived bythe removal of two molecules of hydrogen from adjacent carbon atoms ofthe corresponding alkyl. Alkynyl groups include, but are not limited to,ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl(e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). “Lower alkynyl”refers to alkynyl groups having 2 to 6 carbons.

“Aryl” indicates an aromatic carbon ring having the indicated number ofcarbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groupsmay be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In someinstances, both rings of a polycyclic aryl group are aromatic (e.g.,naphthyl). In other instances, polycyclic aryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to an aromatic ring, provided the polycyclicaryl group is bound to the parent structure via an atom in the aromaticring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein themoiety is bound to the parent structure via an aromatic carbon atom) isconsidered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl(wherein the moiety is bound to the parent structure via a non-aromaticcarbon atom) is not considered an aryl group. Similarly, a1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound tothe parent structure via an aromatic carbon atom) is considered an arylgroup, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moietyis bound to the parent structure via a non-aromatic nitrogen atom) isnot considered an aryl group. However, the term “aryl” does notencompass or overlap with “heteroaryl” regardless of the point ofattachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroarylgroups). In some instances, aryl is phenyl or naphthyl. In certaininstances, aryl is phenyl.

“Aralkyl” refers to “-alkylene-aryl.”

Bivalent radicals formed from substituted benzene derivatives and havingthe free valences at ring atoms are named as substituted phenyleneradicals. Bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., anaphthyl group with two points of attachment is termed naphthylidene.

“Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ringhaving the indicated number of carbon atoms, for example, 3 to 10, or 3to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclicor polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentenyl and cyclohexyl, as wellas bridged and caged ring groups (e.g., norbornane,bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkylgroup may be aromatic, provided the polycyclic cycloalkyl group is boundto the parent structure via a non-aromatic carbon. For example, a1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is a cycloalkylgroup, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety isbound to the parent structure via an aromatic carbon atom) is notconsidered a cycloalkyl group. Examples of polycyclic cycloalkyl groupsconsisting of a cycloalkyl group fused to an aromatic ring are describedbelow.

“Cycloalkenyl” indicates a non-aromatic carbocyclic ring, containing theindicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6ring carbon atoms) and at least one carbon-carbon double bond derived bythe removal of one molecule of hydrogen from adjacent carbon atoms ofthe corresponding cycloalkyl. Cycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groupsinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,and cyclohexenyl, as well as bridged and caged ring groups (e.g.,bicyclo[2.2.2]octene). In addition, one ring of a polycycliccycloalkenyl group may be aromatic, provided the polycyclic alkenylgroup is bound to the parent structure via a non-aromatic carbon atom.For example, inden-1-yl (wherein the moiety is bound to the parentstructure via a non-aromatic carbon atom) is considered a cycloalkenylgroup, while inden-4-yl (wherein the moiety is bound to the parentstructure via an aromatic carbon atom) is not considered a cycloalkenylgroup. Examples of polycyclic cycloalkenyl groups consisting of acycloalkenyl group fused to an aromatic ring are described below.

The term cyano refers to —CN.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Haloalkyl” includes straight and branched carbon chains having theindicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substitutedwith at least one halogen atom. In instances wherein the haloalkyl groupcontains more than one halogen atom, the halogens may be the same (e.g.,dichloromethyl) or different (e.g., chlorofluoromethyl). Examples ofhaloalkyl groups include, but are not limited to, chloromethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-chloroethyl,2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl,pentachloroethyl, and pentafluoroethyl.

“Heteroaryl” indicates an aromatic ring containing the indicated numberof atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of oneor more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, Oand S and with the remaining ring atoms being carbon. Heteroaryl groupsdo not contain adjacent S and O atoms. In some embodiments, the totalnumber of S and O atoms in the heteroaryl group is not more than 2. Insome embodiments, the total number of S and O atoms in the heteroarylgroup is not more than 1. Unless otherwise indicated, heteroaryl groupsmay be bound to the parent structure by a carbon or nitrogen atom, asvalency permits. For example, “pyridyl” includes 2-pyridyl, 3-pyridyland 4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., N⁺—O⁻). Additionally, when sulfur is present ina heteroaryl ring, it may, where the nature of the adjacent atoms andgroups permits, exist in an oxidized state (i.e., S⁺—O⁻ or SO₂).Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic).

In some instances, a heteroaryl group is monocyclic. Examples includepyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole,1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole,oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole),thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine,pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some instances, both rings of a polycyclic heteroaryl group arearomatic. Examples include indole, isoindole, indazole, benzoimidazole,benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole,benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole,1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine,3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine,3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine,1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine,1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine,furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,[1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine,oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine,[1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine,oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine,[1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine,oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,[1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine,thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,[1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine,thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine,[1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine,thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine,[1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine,thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,[1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.,1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine,1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine),imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole,1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

In other instances, polycyclic heteroaryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclicheteroaryl group is bound to the parent structure via an atom in thearomatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered a heteroaryl group, while4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is not considered aheteroaryl group.

“Heteroaralkyl” refers to the group “-alkylene-heteroaryl.”

“Heterocycloalkyl” indicates a non-aromatic, fully saturated ring havingthe indicated number of atoms (e.g., 3 to 10, or 3 to 7, memberedheterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4heteroatoms) selected from N, O and S and with the remaining ring atomsbeing carbon. Heterocycloalkyl groups may be monocyclic or polycyclic(e.g., bicyclic, tricyclic).

Examples of monocyclic heterocycloalkyl groups include oxiranyl,aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

When nitrogen is present in a heterocycloalkyl ring, it may, where thenature of the adjacent atoms and groups permits, exist in an oxidizedstate (i.e., N⁺—O⁻). Examples include piperidinyl N-oxide andmorpholinyl-N-oxide. Additionally, when sulfur is present in aheterocycloalkyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., S⁺—O⁻ or —SO₂—).Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.

In addition, one ring of a polycyclic heterocycloalkyl group may bearomatic (e.g., aryl or heteroaryl), provided the polycyclicheterocycloalkyl group is bound to the parent structure via anon-aromatic carbon or nitrogen atom. For example, a1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic nitrogen atom) is considered aheterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkyl group.

“Heterocycloalkenyl” indicates a non-aromatic ring having the indicatednumber of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl)made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms)selected from N, O and S and with the remaining ring atoms being carbon,and at least one double bond derived by the removal of one molecule ofhydrogen from adjacent carbon atoms, adjacent nitrogen atoms, oradjacent carbon and nitrogen atoms of the correspondingheterocycloalkyl. Heterocycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in aheterocycloalkenyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., N⁺—O⁻).Additionally, when sulfur is present in a heterocycloalkenyl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., S⁺—O⁻ or —SO₂—). Examples of heterocycloalkenylgroups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl,2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl,2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g.,2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl,dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl),tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g.,1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of apolycyclic heterocycloalkenyl group may be aromatic (e.g., aryl orheteroaryl), provided the polycyclic heterocycloalkenyl group is boundto the parent structure via a non-aromatic carbon or nitrogen atom. Forexample, a 1,2-dihydroquinolin-1-yl group (wherein the moiety is boundto the parent structure via a non-aromatic nitrogen atom) is considereda heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkenyl group.

The term “hydroxy” refers to —OH.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined herein. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible, and/or inherentlyunstable.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl (including without limitation C₁-C₄alkyl), cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl,heterocycloalkenyl, and heteroaryl, unless otherwise expressly defined,refer respectively to alkyl, cycloalkyl, cycloalkenyl, aryl,heterocycloalkyl, heterocycloalkenyl, and heteroaryl, wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from: —R^(a), —OR^(b), —O(C₁-C₂alkyl)O— (e.g., methylenedioxy-), —SR^(b), guanidine (—NHC(═NH)NH₂),guanidine wherein one or more of the guanidine hydrogens are replacedwith a C₁-C₄alkyl group, —NR^(b)R^(c), halo, cyano, oxo (as asubstituent for heterocycloalkyl), nitro, —COR^(b), —CO₂R^(b),—CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a), where R^(a) is chosen from C₁-C₆alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R^(b) ischosen from H, C₁-C₆ alkyl, aryl, and heteroaryl; and R^(c) is chosenfrom hydrogen and C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form aheterocycloalkyl group; and where each C₁-C₆ alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl is optionally substituted with one ormore, such as one, two, or three, substituents independently selectedfrom C₁-C₄ alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —OC₁-C₄haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylheteroaryl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo(as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(d) where each R^(d) is independently chosen from: optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted acyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl,sulfinyl and sulfonyl, wherein substituted alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl refer respectively to alkyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more(such as up to 5, for example, up to 3) hydrogen atoms are replaced by asubstituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl;

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —N(C₁-C₄ alkyl)(C₁-C₄alkylheteroaryl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (as asubstitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The terms “substituted” alkyl (including without limitation C₁-C₄alkyl), cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl,heterocycloalkenyl, and heteroaryl, unless otherwise expressly defined,refer respectively to alkyl, cycloalkyl, cycloalkenyl, aryl,heterocycloalkyl, heterocycloalkenyl, and heteroaryl, wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from: —R^(a), —OR^(b), —O(C₁-C₂alkyl)O— (e.g., methylenedioxy-), —SR^(b), guanidine (—NHC(═NH)NH₂),guanidine wherein one or more of the guanidine hydrogens are replacedwith a C₁-C₄alkyl group, —NR^(b)R^(c), halo, cyano, oxo (as asubstituent for heterocycloalkyl), nitro, —COR^(b), —CO₂R^(b),—CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a), where R^(a) is chosen from C₁-C₆alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R^(b) ischosen from H, C₁-C₆ alkyl, aryl, and heteroaryl; and R^(c) is chosenfrom hydrogen and C₁-C₄ alkyl; or R^(b) and R^(c), and the nitrogen towhich they are attached, form a heterocycloalkyl group; and where eachC₁-C₆ alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl isoptionally substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl,aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —C₁-C₄alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylheteroaryl),—NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (as a substitutent forheteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl),—N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl),—C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(aryl), —SO₂(heteroaryl), —SO₂(C₁-C₄haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(aryl),—SO₂NH(heteroaryl), —SO₂(aryl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl),—NHSO₂(aryl), —NHSO₂(heteroaryl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(d) where each R^(d) is independently chosen from: optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted acyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl,sulfinyl and sulfonyl, wherein substituted alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl refer respectively to alkyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more(such as up to 5, for example, up to 3) hydrogen atoms are replaced by asubstituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl;

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylene-aryl, —OC₁-C₄ alkylene-heteroaryl, —C₁-C₄alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄alkylenearyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkyleneheteroaryl), —N(C₁-C₄alkyl)(C₁-C₄ alkylheteroaryl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo(as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(aryl), —N(C₁-C₄ alkyl)C(O)(heteroaryl), —C(O)C₁-C₄alkyl, —C(O)C₁-C₆ aryl, —C(O)heteroaryl, —C(O)C₁-C₄ haloalkyl,—OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(aryl), —SO₂(heteroaryl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(aryl),—SO₂NH(heteroaryl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(aryl),—NHSO₂(heteroaryl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted amino” also refers to the group —NR^(e)R^(f)wherein R^(e) and R^(f), together with the nitrogen to which they arebound, form an optionally substituted 5- to 7-memberednitrogen-containing, non-aromatic, heterocycle which optionally contains1 or 2 additional heteroatoms chosen from nitrogen, oxygen, and sulfur.

“Aminocarbonyl” encompasses a group of the formula —(C═O)(optionallysubstituted amino) wherein substituted amino is as described herein.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. The term “isomers”refers to different compounds that have the same molecular formula. Theterm “stereoisomers” refers to isomers that differ only in the way theatoms are arranged in space. The term “enantiomers” refers tostereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The symbol“(±)” may be used to designate a racemic mixture where appropriate. Theterm “diastereoisomers” refers to stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-Ingold-Prelog R—S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line.

Where compounds described herein exist in various tautomeric forms, theterm “compound” includes all tautomeric forms of the compound. Suchcompounds also include crystal forms including polymorphs andclathrates. Similarly, the term “salt” includes all tautomeric forms andcrystal forms of the compound. The term “tautomers” refers tostructurally distinct isomers that interconvert by tautomerization.Tautomerization is a form of isomerization and includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. Prototropic tautomerization or proton-shift tautomerizationinvolves the migration of a proton accompanied by changes in bond order,often the interchange of a single bond with an adjacent double bond.Where tautomerization is possible (e.g. in solution), a chemicalequilibrium of tautomers can be reached. An example of tautomerizationis keto-enol tautomerization. A specific example of keto-enoltautomerization is the interconversion of pentane-2,4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerizationis phenol-keto tautomerization. A specific example of phenol-ketotautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Pharmaceutically acceptable forms of the compounds recited hereininclude pharmaceutically acceptable salts, and mixtures thereof. In someembodiments, the compounds described herein are in the form ofpharmaceutically acceptable salts.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, haloalkanoate such as trifluoroacetate, andalkanoate such as acetate, HOOC—(CH₂)—COOH where n is 0-4, and likesalts. Similarly, pharmaceutically acceptable cations include, but arenot limited to sodium, potassium, calcium, aluminum, lithium, andammonium. In addition, if the compounds described herein are obtained asan acid addition salt, the free base can be obtained by basifying asolution of the acid salt. Conversely, if the product is a free base, anaddition salt, particularly a pharmaceutically acceptable addition salt,may be produced by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare non-toxic pharmaceuticallyacceptable addition salts.

The term “administering”, as used herein in conjunction with adiagnostic agent, such as, for example, a positron-emitter labeledcompound described herein, means administering directly into or onto atarget tissue or to administer the diagnostic agent systemically to apatient whereby the diagnostic agent is used to image the tissue or apathology associated with the tissue to which it is targeted.“Administering” a composition may be accomplished by injection,infusion, or by either method in combination with other knowntechniques.

The term “Curie” (Ci) is a unit of measurement of radioactivity. One Cirefers to that amount of any radioactive material that will decay at arate of 3.7×10¹⁰ disintegrations per second. The term “milliCurie” (mCi)refers to 10⁻³ Curie. It is understood that the International System(SI) unit of radioactivity, the Becquerel, is equal to onedisintegration/second. Thus one Becquerel=2.7×10⁻¹¹ Curie.

The term “diagnostic imaging”, as used herein, refers to the use ofelectromagnetic radiation to produce images of internal structures ofthe human or animal body for the purpose of diagnosis.

The term “effective amount” of a compound, as used herein, is apredetermined amount calculated to achieve a desired effect such as anamount sufficient to enable the acquisition of a desired image of thetarget organ of an individual. In some instances the target organ is thebrain.

The term “huntingtin protein” or “HTT protein”, as used herein, refersto the protein encoded by the human huntingtin gene (HTT gene) locatedon the short (p) arm of chromosome 4 at position 16.3. More precisely,the IT15 gene coding for the HTT protein is located from base pair3,076,407 to base pair 3,245,686 on chromosome 4.

The term “HTT protein aggregate”, as used herein refers to an insolublefibrous amyloid comprising mis-folded HTT protein molecules.

The term “mutant huntingtin protein” or “mHTT protein” refers topolyglutamine-expanded versions of HTT protein produced due to anexpansion of CAG repeats in the hutingtin gene. This mutant form of HTTprotein is prone to misfolding and aggregate formation.

The term “β-amyloid aggregate”, as used herein refers to an insolublefibrous amyloid comprising mis-folded β-amyloid protein molecules.

The term “imaging agent”, as used herein, refers to a compound asdescribed herein labeled with one or more positron-emitting isotopes orradionuclides. A positron-emitter labeled compound need only be enrichedwith a detectable isotope to a degree that permits detection with atechnique suitable for the particular application.

The term “pathologic process”, as used herein, refers to an alteredendogenous biological process that may be associated with the aberrantproduction and/or functioning of proteins, peptides, RNA and othersubstances associated with such biological process.

The term “PET imaging”, as used herein, refers to the use of apositron-emitter labeled compound to produce images of internalstructures of the human or animal body.

The term “pharmaceutical composition” refers to a composition comprisingat least one imaging agent described herein, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human) Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether a composition has a desiredefficacious outcome based upon the needs of the artisan.

The term “positron-emitting radionuclide”, as used herein, refers to aradio-active isotope that exhibits particular type of radioactive decayreferred to as β+ decay, in which a proton inside a radionuclide nucleusis converted into a neutron while releasing a positron and an electronneutrino (v_(e)). Some examples of positron-emitting radionuclidesinclude ¹⁵O, ¹³N, ¹¹C, ¹⁸F, ⁷⁶Br, and ¹²⁴I. These radionuclides havehalf-lives of about 2, 10, 20, 110 minutes, 16 hours, and 4.2 daysrespectively.

The term “tomography”, as used herein, refers to a process of imaging bysections. The images may be looked at individually, as a series oftwo-dimensional slices or together, as a computer-generatedthree-dimensional representation.

Provided is an imaging agent comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

m is 0, 1, or 2;

n is 1 or 2;

J is C(═O) or —CH₂—;

X is S or N;

Y is CH or N;

Z is CH or N;

W is N or S;

for each occurrence, R₁ is independently chosen from halo, lower alkoxy,hydroxy, aryl, heteroaryl, cycloalkoxy, or lower alkyl, wherein thelower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl are eachoptionally substituted with one, two, or three groups independentlyselected from lower alkoxy, alkenyl, —NR₄R₅, halo, or heteroaryloptionally substituted with one to three lower alkoxy;

R₂ is hydrogen or lower alkyl; and

R₃ is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, or heteroaralkyl, each of which is optionally substitutedwith one, two, or three groups independently chosen from hydroxy, loweralkoxy optionally substituted with lower alkoxy or halo, lower alkyloptionally substituted with halo, halo, heteroaryl, —(CH₂)_(t)NR₄R₅,oxo, cyano, or —C(O)—NR₄R₅, or

R₂ and R₃ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₄R₅;

t is 0, 1, or 2;

each R₄ is independently chosen from hydrogen or lower alkyl;

each R₅ is independently chosen from hydrogen or lower alkyl; or

R₄ and R₅ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₆R₇;

each R₆ is independently hydrogen or lower alkyl; and

each R₇ is independently hydrogen or lower alkyl;

wherein the compound of Formula I, or a pharmaceutically acceptable saltthereof, is labeled with one or more positron-emitting radionuclides.

Some embodiments provide an imaging agent comprising a compound ofFormula I(a):

or a pharmaceutically acceptable salt thereof, wherein

m is 0, 1, or 2;

n is 1 or 2;

X is S or N;

Y is CH or N;

Z is CH or N;

W is N or S;

for each occurrence, R₁ is independently chosen from halo, lower alkoxy,hydroxy, aryl, heteroaryl, cycloalkoxy, or lower alkyl, wherein thelower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl are eachoptionally substituted with one, two, or three groups independentlyselected from lower alkoxy, alkenyl, —NR₄R₅, halo, or heteroaryloptionally substituted with one to three lower alkoxy;

R₂ is hydrogen or lower alkyl; and

R₃ is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, or heteroaralkyl, each of which is optionally substitutedwith one, two, or three groups independently chosen from hydroxy, loweralkoxy optionally substituted with lower alkoxy or halo, lower alkyloptionally substituted with halo, halo, heteroaryl, —(CH₂)_(t)NR₄R₅,oxo, cyano, or —C(O)—NR₄R₅, or

R₂ and R₃ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₄R₅;

t is 0, 1, or 2;

each R₄ is independently chosen from hydrogen or lower alkyl;

each R₅ is independently chosen from hydrogen or lower alkyl; or

R₄ and R₅ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₆R₇;

each R₆ is independently hydrogen or lower alkyl; and

each R₇ is independently hydrogen or lower alkyl;

wherein the compound of Formula I, or a pharmaceutically acceptable saltthereof, is labeled with one or more positron-emitting radionuclides.

Provided is an imaging agent comprising a compound of Formula I(b):

or a pharmaceutically acceptable salt thereof, wherein

m is 0, 1, or 2;

n is 1 or 2;

X is S or N;

Y is CH or N;

Z is CH or N;

for each occurrence, R₁ is independently chosen from lower alkoxy,hydroxy, and lower alkyl;

R₂ is chosen from hydrogen and lower alkyl; and

R₃ is chosen from aryl, aralkyl, heterocycloalkyl, heteroaryl, andheteroaralkyl, each of which is optionally substituted with one, two, orthree groups independently chosen from hydroxy, lower alkoxy, loweralkyl, halo, and —C(O)—NR₄R₅, or

R₂ and R₃ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, and —C(O)—NR₄R₅;

R₄ is chosen from hydrogen and lower alkyl;

R₅ is chosen from hydrogen and lower alkyl; or

R₄ and R₅ taken together with the nitrogen to which they are bound forma heterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, and —C(O)—NR₆R₇,

R₆ is chosen from hydrogen and lower alkyl; and

R₇ is chosen from hydrogen and lower alkyl;

wherein the compound of Formula I, or a pharmaceutically acceptable saltthereof, is labeled with one or more positron-emitting radionuclides.

In some embodiments, X is S. In some embodiments, X is N.

In some embodiments, Y is CH. In some embodiments, Y is N.

In some embodiments, Z is CH. In some embodiments, Z is N.

In some embodiments, W is N. In some embodiments, W is S.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, t is 0. In some embodiments, t is 1. In someembodiments, t is 2.

In some embodiments, for each occurrence, R₁ is independently chosenfrom halo, lower alkoxy, hydroxy, aryl, heteroaryl, or lower alkyl,wherein the lower alkoxy, lower alkyl, aryl, or heteroaryl are eachoptionally substituted with one to two groups independently selectedfrom lower alkoxy, alkenyl, —NR₄R₅, halo, or heteroaryl optionallysubstituted with one to two lower alkoxy.

In some embodiments, for each occurrence, R₁ is independently selectedfrom lower alkoxy, aryl, heteroaryl or lower alkyl, each of which isoptionally substituted with one, two, or three groups independentlyselected from selected from lower alkoxy, alkenyl, —NR₄R₅, halo, orheteroaryl optionally substituted with alkoxy.

In some embodiments, for each occurrence, R₁ is independently selectedfrom halo, lower alkoxy, hydroxy, or lower alkyl, wherein the loweralkoxy or lower alkyl are each optionally substituted with one, two, orthree groups independently selected from alkoxy, alkenyl, —NR₄R₅, halo,or heteroaryl optionally substituted with alkoxy.

In some embodiments, for each occurrence, R₁ is independently selectedfrom hydroxy, lower alkoxy, or lower alkyl, wherein the lower alkoxy orlower alkyl are each optionally substituted with one, two, or threegroups independently selected from alkoxy, alkenyl, —NR₄R₅, or halo.

In some embodiments, for each occurrence, R₁ is independently selectedfrom lower alkoxy optionally substituted with one, two, or three groupsindependently selected alkenyl, halo, or heteroaryl optionallysubstituted with alkoxy.

In some embodiments, for each occurrence, R₁ is independently selectedfrom methoxy or hydroxy.

In some embodiments, m is 1 and R₁ is methoxy.

In some embodiments, for each occurrence, R₁ is independently selectedfrom bromo, methoxy, 2-fluoroethoxy, prop-2-en-1-yloxy,(dimethylamino)methyl, phenyl, 5-methoxypyridin-3-yl,(5-methoxypyridin-2-yl)methoxy, or hydroxy.

In some embodiments, R₂ is hydrogen. In some embodiments, R₂ is methyl.

In some embodiments, R₃ is alkyl, aryl, heterocycloalkyl,heterocycloalkenyl, or heteroaryl, heteroaralkyl, each of which isoptionally substituted with one, two, or three groups independentlychosen from hydroxy, lower alkoxy optionally substituted with loweralkoxy or halo, halo, lower alkyl optionally substituted with halo,halo, heteroaryl, —(CH₂)_(t)NR₄R₅, cyano, or —C(O)—NR₄R₅.

In some embodiments, R₃ is heterocycloalkyl, heterocycloalkenyl, orheteroaryl, each of which is optionally substituted with one, two, orthree groups independently chosen from hydroxy, lower alkoxy optionallysubstituted with lower alkoxy, halo, lower alkyl optionally substitutedwith halo, halo, heteroaryl, —(CH₂)_(t)NR₄R₅, cyano, or —C(O)—NR₄R₅.

In some embodiments, R₃ is heterocycloalkyl or heteroaryl, each of whichis optionally substituted with one, two, or three groups independentlychosen from hydroxy, lower alkoxy optionally substituted with loweralkoxy, halo, lower alkyl optionally substituted with halo, halo,heteroaryl, —(CH₂)_(t)NR₄R₅, cyano, or —C(O)—NR₄R₅.

In some embodiments, R₃ is pyridin-3-yl, pyridin-3-ylmethyl,1-benzofuran-5-yl, 1H-pyrazol-4-yl, or 6-oxo-1,6-dihydropyridazin-3-yl,each of which is optionally substituted with one, two, or three groupsindependently chosen from hydroxy, lower alkoxy, lower alkyl, halo, and—C(O)—NR₄R₅.

In some embodiments, R₃ is pyridin-3-yl, pyridin-3-ylmethyl,1-benzofuran-5-yl, 1H-pyrazol-4-yl, 6-oxo-1,6-dihydropyridazin-3-yl,pyrimidin-5-yl, ethyl, 6-oxo-1,6-dihydropyridin-3-yl, pyridin-2-yl,pyridin-4-yl, pyrazin-2-yl, 2-oxo-1,2-dihydropyrimidin-5-yl, or phenyl,each of which is optionally substituted with one, two, or three groupsindependently chosen from hydroxy, lower alkoxy optionally substitutedwith lower alkoxy, lower alkyl optionally substituted with halo, halo,heteroaryl, —(CH₂)_(t)NR₄R₅, cyano, or —C(O)—NR₄R₅.

In some embodiments, R₃ is pyridin-3-yl, 5-methoxypyridin-3-yl,6-methoxypyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,6-(methylcarbamoyl)pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, or 1-methyl-1H-pyrazol-4-yl.

In some embodiments, R₃ is pyridin-3-yl, 5-methoxypyridin-3-yl,6-methoxypyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,6-(methylcarbamoyl)pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 1-methyl-1H-pyrazol-4-yl,2-methylpyrimidin-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl,2-(dimethylamino)ethyl, 2-methoxyethyl, 6-oxo-1,6-dihydropyridin-3-yl,5-(pyridin-3-yl)pyridin-2-yl, 6-(methylcarbamoyl)pyridin-3-yl,6-oxo-1,6-dihydropyridazin-3-yl, 2-methoxypyridin-4-yl,5,6-dimethoxypyridin-3-yl, 3-cyanopyridin-4-yl,3-cyano-2-methoxypyridin-4-yl, 5-methoxypyridin-2-yl, pyridin-4-yl,pyrazin-2-yl, 3-pyridinyl-1-oxide,1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl, 3-[(methylamino)methyl]phenyl,5-(2-methoxyethoxy)pyridin-3-yl, 6-(2-methoxyethoxy)pyridin-3-yl,(pyridin-3-yl)methyl, 2,6-dimethoxypyridin-3-yl,6-fluoro-5-methoxypyridin-3-yl, 5-(2-fluoroethoxy)pyridin-3-yl,6-(2-fluoroethoxy)pyridin-3-yl,1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridazin-3-yl, or2-methoxypyrimidin-5-yl.

In some embodiments, R₃ is pyridin-3-yl, 5-methoxypyridin-3-yl,6-methoxypyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,6-(methylcarbamoyl)pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 1-methyl-1H-pyrazol-4-yl,2-methylpyrimidin-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl,2-(dimethylamino)ethyl, 2-methoxyethyl, 6-oxo-1,6-dihydropyridin-3-yl,5-(pyridin-3-yl)pyridin-2-yl, 6-(methylcarbamoyl)pyridin-3-yl,6-oxo-1,6-dihydropyridazin-3-yl, 2-methoxypyridin-4-yl,5,6-dimethoxypyridin-3-yl, 3-cyanopyridin-4-yl,3-cyano-2-methoxypyridin-4-yl, 5-methoxypyridin-2-yl, pyridin-4-yl,pyrazin-2-yl, 3-pyridinyl-1-oxide,1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl, 3-[(methylamino)methyl]phenyl,5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl.

In some embodiments, R₂ and R₃ taken together with the nitrogen to whichthey are bound form a heterocycloalkyl ring is2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl, indolin-1-yl,4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl, or4,6-dihydropyrrolo[3,4-b]pyrrol-5(1H)-yl, each of which is optionallysubstituted with one, two, or three groups independently chosen fromhydroxy, lower alkoxy, lower alkyl, and halo.

In some embodiments, each R₄ is independently chosen from hydrogen orC₁₋₃alkyl. In some embodiments, each R₄ is independently chosen fromhydrogen or methyl.

In some embodiments, each R₅ is independently chosen from hydrogen orC₁₋₃alkyl. In some embodiments, each R₅ is independently chosen fromhydrogen or methyl.

In some embodiments, each R₆ is independently chosen from hydrogen orC₁₋₃alkyl. In some embodiments, each R₆ is independently chosen fromhydrogen or methyl.

In some embodiments, each R₇ is independently chosen from hydrogen orC₁₋₃alkyl. In some embodiments, each R₇ is independently chosen fromhydrogen or methyl.

Also provided is an imaging agent comprising a compound of FormulaII(a):

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, m, n,and X are as described for compounds of Formula I and wherein thecompound of Formula II(a), or a pharmaceutically acceptable saltthereof, is labeled with one or more positron-emitting radionuclides.

Also provided is an imaging agent comprising a compound of FormulaII(b):

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, m, n,and X are as described for compounds of Formula I and wherein thecompound of Formula II(b), or a pharmaceutically acceptable saltthereof, is labeled with one or more positron-emitting radionuclides.

Also provided is an imaging agent comprising a compound chosen from:

-   -   10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;    -   N-(6-fluoropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;    -   10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   N-(6-fluoropyridin-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-(pyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;    -   10-methoxy-N-(6-methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;    -   10-methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;        and    -   10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide,    -   or a pharmaceutically acceptable salt thereof, wherein the        compound of Formula I, or a pharmaceutically acceptable salt        thereof, is labeled with one or more positron-emitting        radionuclides.

Also provided is an imaging agent comprising a compound chosen from:

-   10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-fluoropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(6-fluoropyridin-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;-   10-methoxy-N-(6-methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;-   10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-[2-(dimethylamino)ethyl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(2-methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(6-oxo-1,6-dihydropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-[5-(pyridin-3-yl)pyridin-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   5-methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyanopyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(5,6-dimethoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene;-   4-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyano-2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   10-methoxy-N-(5-methoxypyridin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyridin-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyrazin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate;-   10-(2-fluoroethoxy)-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-({10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaen-4-yl}methyl)pyridin-3-amine;-   10-[(5-methoxypyridin-2-yl)methoxy]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   11-bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(2-methylpyrimidin-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,6,9,11-pentaene-4-carboxamide;-   N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   11-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   11-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-{3-[(methylaminomethyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   10-[(dimethylamino)methyl]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(5-methoxypyridin-3-yl)-10-phenyl-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N,5-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N,4-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[5-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide    and-   N-[6-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;    or-   or a pharmaceutically acceptable salt thereof, wherein the compound,    or a pharmaceutically acceptable salt thereof, is labeled with one    or more positron-emitting radionuclides.-   Also provided is an imaging agent comprising a compound chosen from:-   10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-fluoropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(6-fluoropyridin-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;-   10-methoxy-N-(6-methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;-   10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-[2-(dimethylamino)ethyl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(2-methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(6-oxo-1,6-dihydropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-[5-(pyridin-3-yl)pyridin-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   5-methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyanopyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(5,6-dimethoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene;-   4-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyano-2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   10-methoxy-N-(5-methoxypyridin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyridin-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(pyrazin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate;-   10-(2-fluoroethoxy)-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-({10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaen-4-yl}methyl)pyridin-3-amine;-   10-[(5-methoxypyridin-2-yl)methoxy]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   11-bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;-   10-methoxy-N-(2-methylpyrimidin-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,6,9,11-pentaene-4-carboxamide;-   N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   11-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   11-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   10-methoxy-N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   10-[(dimethylamino)methyl]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(5-methoxypyridin-3-yl)-10-phenyl-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N,5-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N,4-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[5-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-[2-(dimethylamino)ethyl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(2-methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(6-oxo-1,6-dihydropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-{[3,3′-bipyridine]-6-yl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(5,6-dimethoxypyridin-3-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene;-   N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   5-methoxy-N-(6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(3-cyano-2-methoxypyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(pyridin-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   N-(pyrazin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   3-{7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate;-   5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;-   N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;-   N-(2-methylpyrimidin-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,6,9,11-pentaene-4-carboxamide;-   5-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   5-methoxy-N-[5-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-[(pyridin-3-yl)methyl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-(1-benzofuran-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-(6-fluoropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene;-   4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene;-   N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;-   5-methoxy-N-[6-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(2,6-dimethoxypyridin-3-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-fluoro-5-methoxypyridin-3-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(2-fluoroethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[5-(2-fluoroethoxy)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(2,6-dimethoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(6-fluoro-5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[6-(2-fluoroethoxy)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[5-(2-fluoroethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-[1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridazin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;-   N-(2-methoxypyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;    and-   10-methoxy-N-(2-methoxypyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;    -   or a pharmaceutically acceptable salt thereof, wherein the        compound, or a pharmaceutically acceptable salt thereof, is        labeled with one or more positron-emitting radionuclides.

Also provided herein are compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, that are not labeled with one or morepositron-emitting radionuclides.

The compounds of Formula I, or a pharmaceutically acceptable saltthereof are labeled with one or more positron-emitting radionuclides.Suitable positron-emitting radionuclides that may be incorporated in thecompounds of described herein, but are not limited to, ¹¹C, ¹³N, ¹⁵O,¹⁸F, ⁵²Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁸Ga, ⁷⁴As, ⁸²Rb, ⁸⁹Zr, ¹²²I, and ¹²⁴I. In someembodiments, the one or more positron-emitting radionuclides areselected from: ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁶Br, and ¹²⁴I. In some embodimentsthe one or more positron-emitting radionuclides are selected from ¹¹C,¹³N, ¹⁵O, and ¹⁸F.

Non-metal radionuclides may be covalently linked to the compoundsdescribed herein by a reaction well known from the state of art. Whenthe radionuclide is a metallic positron-emitter, it is understood thatlabeling may require the use of a chelating agent. Such chelating agentsare well known from the state of the art.

A PET imaging agent may be labelled with the positron emitter ¹¹C or¹⁸F. Methods for the introduction of ¹¹C may include, but are notlimited to, alkylation with [¹¹C]iodomethane or [¹¹C]methyl triflate,such as described in the Examples below. Carbon-11 has a half-life ofapproximately 20 minutes, thus ¹¹C needs to be generated in an on-sitecyclotron, and is generally produced as [¹¹C]carbon dioxide. The[¹¹C]carbon dioxide is converted to the chemical species appropriate forthe radiosynthesis (generally [¹¹C]iodomethane or the like), and thesynthesis of the radiopharmaceutical is completed and used on-site in aPET imaging study after the appropriate radiochemical purity andspecific activity have been determined. Typical methods of introducing¹⁸F may include but are not limited to displacement of a halide,tosylate, or other leaving group with [¹⁸F]tetrabutylamonium fluoride or[¹⁸F]potassium fluoride kryptofix-[2.2.2]. Fluorine-18 has a half lifeof approximately 110 minutes, thus synthesis of[¹⁸F]radiopharmaceuticals need not necessarily have to occur at the siteof the cyclotron nor proximal to the PET imaging study center. Generalmethods for the introduction of these positron emitters are described inthe literature (Miller et al., Angewandte Chemie International Edition,47 (2008), 8998-9033). Accordingly, unlabeled analogs of the compoundsdescribed herein can be synthesized as described in the syntheticexamples below and labeled with positron-emitting radionuclidesaccording to the examples below and/or methods as known in the art.

Provided are methods of generating diagnostic images in an individualcomprising administering an effective amount of an imaging agentdescribed herein to an individual, and generating an image of at least apart of the individual.

In some embodiments, generating an image of at least a part of saidindividual comprises generating an image to detect the presence orabsence of huntingtin protein monomers or aggregates in said individual;and detecting the presence or absence of a pathologic process.

In some embodiments, generating an image of at least a part of saidindividual comprises generating an image to detect the presence orabsence of mutant huntingtin protein (mHTT protein) or aggregatesthereof in said individual; and detecting the presence or absence of apathologic process.

Also provided are methods of generating diagnostic images in abiological sample comprising the contacting the biological sample withan effective amount of an imaging agent described herein and generatingan image of the positron-emitter labeled compound associated with thebiological sample. In this method both the contacting and the generatingmay be conducted in vitro, alternatively the contacting is in vivo andthe generating in vitro.

Also provided are diagnostic methods of using the imaging agents tomonitor disease progression in a patient by quantifying the change inlevels of the target aggregates in the patient.

Also provided are methods for detecting the presence or absence of aneurodegenerative pathologic process associated with huntingtin protein(HTT protein) in an individual comprising: administering an effectiveamount of a positron-emitter labeled compound described herein;generating an image to detect the presence or absence of HTT proteinaggregates in the individual; and detecting the presence or absence ofthe pathologic process.

Also provided are methods for detecting the presence or absence of aneurodegenerative pathologic process associated with mutant huntingtinprotein (mHTT protein) in an individual comprising: administering aneffective amount of a positron-emitter labeled compound describedherein; generating an image to detect the presence or absence of mHTTprotein or aggregates thereof in the individual; and detecting thepresence or absence of the pathologic process.

In some embodiments, the HTT protein monomers or aggregates are presentin the brain, liver, heart, or muscle of said individual. In someembodiments, the HTT protein monomers or aggregates are present in thebrain of said individual. In some embodiments, the HTT protein monomersor aggregates are present in the basal ganglia, cortex, hippocampus, orbrain stem of the brain of the individual.

In some embodiments, the mHTT protein or aggregates thereof are presentin the brain, liver, heart, or muscle of said individual. In someembodiments, the mHTT protein or aggregates thereof are present in thebrain of said individual. In some embodiments, the mHTT protein oraggregates thereof are present in the basal ganglia, cortex,hippocampus, or brain stem of the brain of the individual.

In some embodiments, the pathologic process is a neurodegenerativedisease. In some embodiments, the neurodegenerative disease is chosenfrom Alzheimer's disease, amyotrphic lateral sclerosis, Huntington'sdisease, Parkinson's disease, Prion disease, or spinocerebellar ataxias.

In some embodiments, the pathologic process is Huntington's disease(HD).

In some embodiments, the effective amount of the imaging agent comprisesfrom about 0.1 to about 20 mCi. In some embodiments, the effectiveamount of the imaging agent comprises from about 10 mCi.

In some embodiments, generating an image comprises positron emissiontomography (PET) imaging, PET with concurrent computed tomographyimaging (PET/CT), PET with concurrent magnetic resonance imaging(PET/MRI), or a combination thereof. In some embodiments, generating animage comprises PET imaging.

Also provided are methods for detecting the presence or absence of aneurodegenerative pathologic process associated with β-amyloid proteinin an individual comprising: administering an effective amount of apositron-emitter labeled compound described herein; generating an imageto detect the presence or absence of β-amyloid protein aggregates in theindividual; and detecting the presence or absence of the pathologicprocess. In some embodiments, the β-amyloid protein monomers oraggregates are present in the brain, liver, heart, or muscle of saidindividual. In some embodiments, the β-amyloid protein aggregates arepresent in the basal ganglia, cortex, hippocampus, or brain stem of thebrain of the individual. In some embodiments, the pathologic process isAlzheimer's Disease (AD). In some embodiments, the effective amount ofthe imaging agent comprises from about 0.1 to about 20 mCi. In someembodiments, the effective amount of the imaging agent comprises fromabout 10 mCi. In some embodiments, generating an image comprisespositron emission tomography (PET) imaging, PET with concurrent computedtomography imaging (PET/CT), PET with concurrent magnetic resonanceimaging (PET/MRI), or a combination thereof. In some embodiments,generating an image comprises PET imaging.

Provided herein are compounds having suitable HTT protein aggregate orβ-amyloid protein aggregate binding kinetics to function as efficientimaging agents for HTT or protein aggregates or β-amyloid proteinaggregates. The requirements of the compounds of the invention tofunction as efficient imaging agents for HTT protein aggregates are: 1)a high affinity for HTT protein aggregates; 2) a low affinity for nearbystructures; 3) slow dissociation kinetics from HTT protein aggregates,which may conveniently be expressed as the dissociation rate constantk_(diss) as defined in the following equation, wherein A and B refer tothe HTT or mHTT protein aggregate and the imaging agent, and k_(assn) isthe association rate constant.d[AB]/dt=k _(assn)[A][B]−k _(diss)[AB]

Provided herein are compounds having suitable mHTT protein aggregate orβ-amyloid protein aggregate binding kinetics to function as efficientimaging agents for mHTT protein aggregates or β-amyloid proteinaggregates. The requirements of the compounds of the invention tofunction as efficient imaging agents for mHTT protein aggregates are: 1)a high affinity for mHTT protein aggregates; 2) a low affinity fornearby structures; 3) slow dissociation kinetics from mHTT proteinaggregates, which may conveniently be expressed as the dissociation rateconstant k_(diss) as defined in the following equation, wherein A and Brefer to the mHTT protein aggregate and the imaging agent, and k_(assn)is the association rate constant.d[AB]/dt=k _(assn)[A][B]−k _(diss)[AB]

The part of the brain most affected by HD, and thus most likely tocontain HTT protein abnormalities (i.e. mHTT protein), is a group ofnerve cells at the base of the brain known collectively as the basalganglia. The basal ganglia organize muscle-driven movements of the body,or “motor movement.” The major components of the basal ganglia are thecaudate and the putamen (together known as the striatum) and the globuspallidus (external and internal regions). The substantia nigra and thesubthalamic nucleus are often included as part of the basal ganglia aswell.

The term basal ganglia, refers to a group of subcortical nucleiresponsible primarily for motor control, as well as other roles such asmotor learning, executive functions and behaviors, and emotions.Disruption of the basal ganglia network forms the basis for severalmovement disorders. Normal function of the basal ganglia requires finetuning of neuronal excitability within each nucleus to determine theexact degree of movement facilitation or inhibition at any given moment.This is mediated by the complex organization of the striatum, where theexcitability of medium spiny neurons is controlled by several pre- andpostsynaptic mechanisms as well as interneuron activity, and secured byseveral recurrent or internal basal ganglia circuits. The motor circuitof the basal ganglia has two entry points, the striatum and thesubthalamic nucleus, and an output, the globus pallidus pars interna,which connects to the cortex via the motor thalamus.

Provided are methods for imaging part of the brain of an individualinvolving administering a positron-emitter labeled compound describedherein to the individual, e.g. into the individual's vascular system,from where it passes through the blood-brain barrier, and thengenerating an image of at least the part of the individual's brain towhich the compound has distributed.

Also provided are pharmaceutical compositions comprising an effectiveamount of a positron-emitter labeled compound described herein, or asalt thereof, together with one or more pharmaceutically-acceptableadjuvants, excipients or diluents.

Also provided are pharmaceutical compositions comprising an effectiveamount of a positron-emitter labeled compound described herein, or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable adjuvants, excipients or diluents.

An imaging agent or pharmaceutical composition thereof may beadministered to a patient in need of treatment via any suitable route.Routes of administration may include, for example, parenteraladministration (including subcutaneous, intramuscular, intravenous, bymeans of, for example a drip patch). Further suitable routes ofadministration include (but are not limited to) oral, rectal, nasal,topical (including buccal and sublingual), infusion, vaginal,intradermal, intraperitoneally, intracranially, intrathecal and epiduraladministration or administration via oral or nasal inhalation, by meansof, for example a nebulizer or inhaler, or by an implant.

An imaging agent or pharmaceutical composition thereof may also beadministered via microspheres, liposomes, other microparticulatedelivery systems or sustained release formulations placed in certaintissues including blood. Suitable examples of sustained release carriersinclude semi-permeable polymer matrices in the form of shared articles,e.g., suppositories or microcapsules. Examples of the techniques andprotocols mentioned above and other techniques and protocols which maybe used in accordance with the invention can be found in Remington'sPharmaceutical Sciences, 18th edition, Gennaro, A. R., LippincottWilliams & Wilkins; 20th edition (Dec. 15, 2000) ISBN 0-912734-04-3 andPharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, N. C. etal. 7th Edition ISBN 0-683305-72-7, the entire disclosures of which areherein incorporated by reference.

Also provided are uses of positron-emitter labeled compound describedherein for the manufacture of an imaging agent for use in a method ofdiagnosis of an individual.

Provided are methods of generating diagnostic images comprising positronemission tomography (PET). PET involves the administration of apositron-emitting radionuclide tracer to an individual. Once the tracerhas had sufficient time to associate with the target of interest, theindividual is placed in a scanning device comprising a ring ofscintillation detectors. An emitted positron travels through theindividual's tissue for a short (isotope-dependent) distance, until itinteracts with an electron. The interaction annihilates both theelectron and the positron, producing a pair of photons moving inapproximately opposite directions. These are detected when they reach ascintillator in the scanning device. Photons that do not arrive in pairsare ignored.

Also provided are methods of generating diagnostic images comprising PETwith concurrent computed tomography imaging (PET/CT), or with concurrentmagnetic resonance imaging (PET/MRI). Computed tomography uses X-rays toshow the structure of the brain, while magnetic resonance imaging usesmagnetic fields and radio waves.

Other uses of the disclosed imaging agents and methods will becomeapparent to those skilled in the art based upon, inter alia, a review ofthis disclosure.

As will be recognized, the steps of the methods described herein neednot be performed any particular number of times or in any particularsequence. Additional objects, advantages and novel features of thedisclosure will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES

General Experimental Details

Commercially available reagents and solvents (HPLC grade) were usedwithout further purification. ¹H NMR spectra were recorded on a BrukerDRX 500 MHz spectrometer, a Bruker AVANCE 500 MHz spectrometer, a BrukerAVANCE 300 MHz spectrometer or a Bruker DPX 250 MHz spectrometer indeuterated solvents. Chemical shifts (δ) are in parts per million. SCXchromatography was performed with Biotage Isolute Flash SCX-2 loadingthe sample in methanol and eluting with methanol then 5% ammonia inmethanol.

Analytical HPLC-MS (METCR1600), was performed on Hewlett Packard HPLCsystems using reverse phase Phenomenex Gemini C₁₈ columns (2 μm, 2.0×100mm), gradient 5-100% B (A=2 mM ammonium bicarbonate in water buffered topH10, B=acetonitrile) over 5.9 minutes injection volume 3 μL, flow=0.5mL/minute. UV spectra were recorded at 215 nm using a Waters photo diodearray detector. Mass spectra were obtained over the range m/z 150 to 850at a sampling rate of 2 scans per second using a Waters ZQ. Data wereintegrated and reported using OpenLynx software.

Analytical HPLC-MS (METCR1673), was performed on Shimadzu LCMS-2010EVsystems using reverse phase Supelco Ascentis Express (2.7 μm, 2.1×30mm), gradient 5-100% B (A=water/0.1% formic acid, B=acetonitrile/0.1%formic acid) over 1.6 minutes injection volume 3 μL, flow=1.0 mL/minute.UV spectra were recorded at 215 nm using a SPD-M20A photo diode arraydetector. Mass spectra were obtained over the range m/z 100 to 1000 at asampling rate of 2 scans per second using a LCMS2010EV. Data wereintegrated and reported using Shimadzu LCMS-Solutions and PsiPortsoftware.

Alternatively, (METCR1416) analytical HPLC-MS on Shimadzu LCMS-2010EVsystems using reverse phase Water Atlantis dC18 columns (3 μm, 2.1×100mm), gradient 5-100% B (A=water/0.1% formic acid, B=acetonitrile/0.1%formic acid) over 7 minutes, injection volume 3 μL, flow=0.6 mL/minute.UV spectra were recorded at 215 nm using a SPD-M20A photo diode arraydetector. Mass spectra were obtained over the range m/z 150 to 850 at asampling rate of 2 scans per second using a LCMS2010EV. Data wereintegrated and reported using Shimadzu LCMS-Solutions and PsiPortsoftware.

Alternatively, (MET-uHPLC-AB-101) analytical HPLC-MS were performed on aWaters Acquity UPLC system with Waters PDA and ELS detectors using aPhenomenex Kinetex-XB C-18 column, (1.7 μM, 2.1 mm×100 mm at a columntemperature of 40° C., gradient 5-100% B (A=water/0.1% formic acid;B=acetonitrile/0.1% formic acid) over 5.3 minutes, then 100% B for 0.5minutes, flow=0.6 mL/minute. UV spectra were recorded at 215 nm using aWaters Acquity photo diode array. Mass spectra were obtained over therange m/z 150 to 850 at a sampling rate of 5 scans per second using aWaters SQD. Data were integrated and reported using Waters MassLynx andOpenLynx software.

All example compounds display an LC purity of >95% unless statedotherwise.

Method 1 Scheme for Method 1

Step 1, Method 1: Ethyl10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate

6-Methoxy-1,3-benzothiazol-2-amine (5 g, 27.74 mmol) was dissolved indimethoxyethane (60 mL). Ethyl 3-bromo-2-oxopropanoate (3.5 mL, 27.74mmol) was added and the resulting mixture heated to reflux for 18 hours.The mixture was cooled to room temperature and stood for 48 hours. Themixture was filtered and the solid washed with tert-butyl methyl ether(2×10 mL) then dried under suction. The solid was suspended in water andthe mixture adjusted to pH 9 with ammonium hydroxide solution. Themixture was filtered and the solid washed with tert-butyl methyl ether(100 mL) then dried under suction to give a tan powder (4.8 g). 1.45 gwas purified by column chromatography (silica, 12-100% ethyl acetate inheptane) to give the title compound 122 mg (2% yield) as a yellowpowder. ¹H NMR (500 MHz, DMSO) 8.96 (s, 1H), 8.08 (d, J=8.9 Hz, 1H),7.69 (d, J=2.5 Hz, 1H), 7.15 (dd, J=8.9, 2.5 Hz, 1H), 4.29 (q, J=7.1 Hz,2H), 3.83 (s, 3H), 1.31 (t, J=7.1 Hz, 3H). Tr(MET-uHPLC-AB-101)=2.8 min,m/z (ES⁺) (M+H)⁺ 277.

Step 2, Method 1:10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid

Ethyl10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(250 mg, 0.9 mmol) was suspended in dioxane (10 mL), 2 M sodiumhydroxide (0.45 mL, 0.91 mmol) was added and the mixture stirred at roomtemperature for 30 minutes. Additional 2 M sodium hydroxide (0.5 mL) wasadded and stirring continued overnight. The reaction mixture wasacidified with 1 M hydrochloric acid (10 mL) and the precipitatecollected by filtration. The precipitate was dissolved in methanol andconcentrated in vacuo to give the title compound 190 mg (85% yield) as abeige solid. ¹H NMR (500 MHz, DMSO) 12.59 (br. s, 1H), 8.88 (s, 1H),8.06 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.15 (dd, J=8.9, 2.5 Hz,1H), 3.83 (s, 3H). Tr(METCR1673)=0.98 min, m/z (ES⁺) (M+H)⁺ 249.

Step 3, Method 1:10-Methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (190 mg, 0.77 mmol), pyridin-3-amine (79 mg, 0.84 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (320.1 mg, 0.84 mmol) andethyldiisopropylamine (0.4 mL, 2.3 mmol) were dissolved inN,N-dimethylformamide (5 mL) and stirred at room temperature for 40hours under nitrogen. The solvents were removed in vacuo and the residuepartitioned between water (20 mL) and ethyl acetate (100 mL), themixture was filtered and the precipitate dried under suction to give thetitle compound 136 mg (55% yield) as a white solid.

Example 1, Method 1:10-Methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.47 (s, 1H), 9.04 (d, J=2.3 Hz, 1H), 8.98 (s,1H), 8.34-8.23 (m, 2H), 8.11 (d, J=8.9 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H),7.47-7.30 (m, 1H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 3.84 (s, 3H).Tr(MET-uHPLC-AB-101)=1.92 min, m/z (ES⁺) (M+H)⁺ 325.

The following examples were prepared using Method 1, or similar methodsthereof, described above.

TABLE 1 Mol. Ex. Structure Weight IUPAC Name LCMS data  1

324.36 10-methoxy-N- (pyridin-3-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 1.92 min, m/z (ES⁺) (M + H)⁺ 325  2

354.38 10-methoxy-N-(6- methoxypyridin-3- yl)-7-thia-2,5-diazatricyc1o[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 3.08 min, m/z (ES⁺) (M + H)⁺ 355  3

338.38 10-methoxy-N- (pyridin-3- ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(METCR1416 Hi res 7 min) = 2.78 min, m/z (ES⁺) (M + H)⁺339  4

338.38 10-methoxy-N- methyl-N-(pyridin- 3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 1.95 min, m/z (ES⁺) (M + H)⁺ 339  5

363.39 N-(1-benzofuran-5- yl)-10-methoxy-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamide Tr(MET-uHPLC-AB- 101) = 3.63 min, m/z (ES⁺) (M + H)⁺ 364  6

327.36 10-methoxy-N-(1- methyl-1H-pyrazol 4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 2.47 min, m/z (ES⁺) (M + H)⁺ 328  7

339.37 10-methoxy-N-(2- methylpyrimidin-5- yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(METCR 1600) = 3.95 min, m/z (ES⁺) (M + H)⁺ 340  8

390.42 N-[6-(1H-imidazol- 1-yl)pyridin-3-yl]- 10-methoxy-7-thia-2,5-diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 1.92 min, m/z (ES⁺) (M + H)⁺ 391  9

325.35 10-methoxy-N- (pyrimidin-5-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 2.42 min, m/z (ES⁺) (M + H)⁺ 326 10

318.40 N-[2- (dimethylamino) ethyl]-10-methoxy-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- Tr(MET- uHPLC-AB-101) = 1.41 min, m/z (ES⁺) (M + H)⁺ 319 carboxamide 11

305.35 10-methoxy-N-(2- methoxyethyl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamide Tr(MET-uHPLC-AB- 101) = 2.41 min, m/z (ES⁺) (M + H)⁺ 306 12

340.36 10-methoxy-N-(6- oxo-1,6- dihydropyridin-3- yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4- Tr(METCR1600) = 3.52 min, m/z (ES⁺) (M + H)⁺ 341 carboxamide 13

401.44 10-methoxy-N-[5- (pyridin-3- yl)pyridin-2-yl]-7-thia-2,5-diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 2.62 min, m/z (ES⁺) (M + H)⁺ 402 14

341.35 10-methoxy-N-(6- oxo-1,6- dihydropyridin-3- yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4- Tr(MET-uHPLC-AB- 101) = 2.21 min, m/z (ES⁺) (M + H)⁺ 342 carboxamide 15

310.38 N-({10-methoxy-7- thia-2,5- diazatricyclo [6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10- pentaene-4- yl}methyl)pyridin-3- amine

Method 2 Scheme for Method 2

Step 1, Method 2:10-Hydroxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,9,11-tetraene-4-carboxylicacid

10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,9,11-tetraene-4-carboxylicacid (638 mg, 2.57 mmol, prepared by Method 1) was suspended indichloromethane (50 mL) and stirred for five minutes. 1 M tribromoboranein dichloromethane (10 mL, 10.28 mmol) was added and the reaction wasstirred for 2 hours. The reaction mixture was quenched with water (100mL) and concentrated in vacuo. Trituration with acetonitrile (5 mL) gavethe title compound 821 mg (100% yield, 74% purity) as a red solid. ¹HNMR (500 MHz, DMSO) 9.97 (s, 1H), 8.84 (s, 1H), 7.95 (d, J=8.8 Hz, 1H),7.40 (d, J=2.3 Hz, 1H), 6.96 (dd, J=8.8, 2.4 Hz, 1H). Tr(METCR1673)=0.77min, m/z (ES⁺) (M+H)⁺ 235.

Step 2, Method 2:10-Hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,9,11-tetraene-4-carboxamide

10-Hydroxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,9,11-tetraene-4-carboxylicacid (400 mg, 1.71 mmol), 6-methoxypyridin-3-amine (0.2 mL, 1.87 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (714 mg, 1.87 mmol) andethyldiisopropylamine (0.9 mL, 5.12 mmol) were dissolved inN,N-dimethylformamide (15 mL) and stirred at room temperature for 18hours. The reaction mixture was added to water (100 mL) and brine (100mL) and extracted with ethyl acetate (3×200 mL). The extracts werecombined, washed with brine (100 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. Recrystallisation from 2:1acetonitrile:water (50 mL) gave the title compound 60 mg (10% yield) asa brown solid.

Example 1, Method 2:10-Hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,9,11-tetraene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.22 (s, 1H), 10.08 (s, 1H), 8.85 (s, 1H), 8.61(d, J=2.6 Hz, 1H), 8.15 (dd, J=8.9, 2.7 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H),7.41 (d, J=2.3 Hz, 1H), 6.97 (dd, J=8.7, 2.4 Hz, 1H), 6.82 (d, J=8.9 Hz,1H), 3.83 (s, 3H). Tr(MET-uHPLC-AB-101)=2.48 min, m/z (ES⁺) (M+H)⁺ 341,94%.

The following examples were prepared using Method 2 described above:

TABLE 2 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

340.36 10-hydroxy-N-(6- methoxypyridin- 3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 2.48 min, m/z (ES⁺) (M + H)⁺ 341 2

310.33 10-methoxy-N- (pyridin-3-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET- uHPLC-AB- 101) = 1.43 min, m/z (ES⁺) (M + H)⁺ 311

Method 3 Scheme for Method 3

Step 1, Method 3: Ethyl1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate

1H-Benzimidazol-2-amine (2 g, 15.02 mmol) and ethyl(3E)-4-(dimethylamino)-2-oxobut-3-enoate (70%, 4 g, 16.36 mmol,described in US2011001121) were suspended in acetic acid (50 mL) and thereaction heated at 120° C. for 16 hours. The reaction mixture was cooledto room temperature and the solvents removed in vacuo. The residue wasbasified with saturated sodium bicarbonate solution (50 mL). The mixturewas partitioned with ethyl acetate (150 mL) and the biphasic mixturefiltered. The phases were separated and the aqueous further extractedwith ethyl acetate (2×100 mL). The combined organics were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo.Purification by FCC (silica, 40-100% ethyl acetate in heptane) gave thetitle compound 360 mg (10% yield) as a yellow powder. ¹H NMR (500 MHz,DMSO) 9.73 (d, J=7.0 Hz, 1H), 8.42 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.3 Hz,1H), 7.74-7.59 (m, 2H), 7.59-7.38 (m, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.40(t, J=7.1 Hz, 3H). Tr(METCR1673)=0.96 min, m/z (ES⁺) (M+H)⁺ 242.

Step 2, Method 3:1,8,10-Triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid

Ethyl1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate(360 mg, 1.45 mmol) was suspended in tetrahydrofuran (10 mL), 2 M sodiumhydroxide (1.5 mL) added and the reaction was stirred at roomtemperature for 2 hours. The tetrahydrofuran was removed in vacuo andthe residue acidified with 1 M hydrogen chloride (2 mL), adjusting thepH to 4-5. The solvents were removed in vacuo and the product azeotropedwith toluene (2×20 mL) to give the title compound 440 mg (100% yield) asa yellow powder. ¹H NMR (500 MHz, DMSO) 9.56 (d, J=6.9 Hz, 1H), 8.34 (d,J=8.2 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.59-7.52 (m, 2H), 7.44 (appt t,J=7.7 Hz, 1H). Tr(METCR1673)=0.27 min, m/z (ES⁺) (M+H)⁺ 214, 49%.

Step 3, Method 3:N-(6-Methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

1,8,10-Triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid (100 mg, 0.42 mmol), 6-methoxypyridin-3-amine (63 mg, 0.51 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (192.62 mg, 0.51 mmol) andethyldiisopropylamine (0.22 mL, 1.27 mmol) were dissolved in anhydrousN,N-dimethylformamide (5 mL) and the reaction stirred at roomtemperature for 16 hours. The reaction mixture was evaporated and theresidue partitioned between ethyl acetate (20 mL) and water (20 mL). Themixture was filtered through glass fibre filter paper and theprecipitate dried in vacuo to give the title compound 27 mg (20% yield)as a green solid.

Example 1, Method 3:N-(6-Methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 11.06 (s, 1H), 9.77 (d, J=7.0 Hz, 1H), 8.71 (d,J=2.6 Hz, 1H), 8.43 (d, J=8.2 Hz, 1H), 8.22 (dd, J=8.9, 2.7 Hz, 1H),7.96 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.64 (appt t, J=7.7 Hz,1H), 7.53 (appt t, J=7.7 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H), 3.87 (s, 3H).Tr(MET-uHPLC-AB-101)=2.19 min, m/z (ES⁺) (M+H)⁺ 320.

The following examples were prepared using Method 3 described above:

TABLE 3 Mol. Ex. Structure Weight IUPAC Name LCMS data  1

319.32 N-(6- methoxypyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET-uHPLC- AB 101) = 2.19 min, m/z (ES⁺) (M + H)⁺ 320  2

307.28 N-(6- fluoropyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET-uHPLC- AB-101) = 2.17 min, m/z (ES⁺) (M + H)⁺ 308  3

346.35 N-[6- (methylcarbamoyl) pyridin-3-yl]- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- Tr(MET-uHPLC- AB-101) = 1.95min, m/z (ES⁺) (M + H)⁺ 347 hexaene-11- carboxamide  4

319.32 N-(5- methoxypyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET-uHPLC- AB-101) = 1.76 min, m/z (ES⁺) (M + H)⁺ 320  5

320.31 N-(1-methyl-6- oxo-1,6- dihydropyridazin- 3-yl)-1,8,10-triazatricyclo [7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11-Tr(MET-uHPLC- AB-101) = 1.65 min, m/z (ES⁺) (M + H)⁺ 321 carboxamide  6

305.30 N-(6-oxo-1,6- dihydropyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- Tr(MET-uHPLC-AB-101) = 1.39 min, m/z (ES⁺) (M + H)⁺ 306 carboxamide  7

289.30 N-(pyridin-3-yl)- 1,8,10- triazatricyclo [7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12- hexaene-11- carboxamide Tr(MET-uHPLC- AB-101) = 1.36min, m/z (ES⁺) (M + H)⁺ 290  8

314.31 N-(3- cyanopyridin-4- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET-uHPLC- AB-101) = 2.19 min, m/z (ES⁺) (M + H)⁺ 315  9

319.32 N-(2- methoxypyridin-4- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- Tr(MET-uHPLC-AB-101) = 2.08 min, m/z (ES⁺) (M + H)⁺ 320 carboxamide 10

349.35 N-(5,6- dimethoxypyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- Tr(MET-uHPLC-AB-101) = 2.2 min, m/z (ES⁺) (M + H)⁺ 350 carboxamide 11

306.29 N-(6-oxo-1,6- dihydropyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET-uHPLC- AB-101) = 1.48 min, m/z (ES⁺) (M + H)⁺ 307 12

344.33 N-(3-cyano-2- methoxypyridin-4- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(METCR1603) = 3.76 min, m/z (ES⁺) (M + H)⁺ 345

Method 4 Scheme for Method 4

Step 1, Method 4:10-Methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (95%, 100 mg, 0.38 mmol, described in Method 1) and5-amino-N-methylpyridine-2-carboxamide (58 mg, 0.38 mmol, as prepareddescribed in PCT Int. Appl., 2008056150) in pyridine (2 mL) were stirredat room temperature for 20 minutes.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46mmol) was added and the reaction was stirred at room temperatureovernight under nitrogen. 5-Amino-N-methylpyridine-2-carboxamide (27 mg,0.19 mmol) was added and the mixture stirred at room temperature for 20minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44mg, 0.23 mmol) was added and the mixture stirred at room temperature for2 days. The mixture was heated to 60° C. for 4 hours. The mixture wasdiluted with pyridine (2 mL) filtered, washed with water (2 mL),methanol (2 mL) and heptane (2 mL). Recrystallization from DMSO (1.5 mLand then 2.5 mL) gave the title compound 30 mg (20% yield) as a whitepowder.

Example 1, Method 4:10-Methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.69 (s, 1H), 9.11 (d, J=2.4 Hz, 1H), 9.00 (s,1H), 8.65 (q, J=4.6 Hz, 1H), 8.49 (dd, J=8.6, 2.5 Hz, 1H), 8.12 (d,J=8.9 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.19 (dd,J=8.9, 2.5 Hz, 1H), 3.85 (s, 3H), 2.81 (d, J=4.8 Hz, 3H).Tr(MET-uHPLC-AB-101)=2.77 min, m/z (ES⁺) (M+H)⁺ 382.

The following examples were prepared using Method 4 described above:

TABLE 4 Mol. Ex. Structure Weight IUPAC Name LCMS data  1

381.41 10-methoxy-N-[6- (methylcarbamoyl) pyridin-3-yl]-7-thia-2,5-diazatricyclo [6.4.0.0 ^(2,) ⁶ ]dodeca- 1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET-uHPLC- AB-101) = 2.77 min, m/z (ES⁺) (M + H)⁺ 382  2

350.39 10-methoxy-4- {1H,2H,3H- pyrrolo[2,3-c] pyridine-l-carbonyl}-7-thia- 2,5-diazatricyclo [6.4.0.0^(2,6)]dodeca- Tr(MET-uHPLC-AB-101) = 1.86 min, m/z (ES⁺) (M + H)⁺ 351 1(12),3,5,8,10- pentaene  3

338.38 10-methoxy-N-(6- methylpyridin-3-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamideTr(MET-uHPLC- AB-101) = 1.83 min, m/z (ES⁺) (M + H)⁺ 339  4

353.40 10-methoxy-4- {1-methyl- 1H,4H,5H,6H- pyrrolo[3,4-c] pyrazole-5-carbonyl}-7-thia- 2,5-diazatricyclo [6.4.0.0 ^(2,) ⁶ ]dodeca-1(12),3,5,8,10- pentaene Tr(METCR1600) = 3.64 min, m/z (ES⁺) (M + H)⁺354  5

354.38 10-methoxy-N-(5- methoxypyridin-3- yl)-7-thia-2,5- diazatricyclo[6.4.0.0 ^(2,) ⁶ ]dodeca- 1(12),3,5,8,10 Tr(MET-uHPLC- AB-101) = 2.43min, m/z (ES⁺) (M + H)⁺ 355 pentaene-4- carboxamide  6

342.35 N-(6-fluoropyridin- 3-yl)-10-methoxy-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamideTr(MET-uHPLC- AB-101) = 3.07 min, m/z (ES⁺) (M + H)⁺ 343  7

325.35 10-methoxy-N- (pyridin-3-yl)-7- thia-2,5,9- triazatricyclo[6.4.0.0^(2,6)] dodeca- 1(12),3,5,8,10- Tr(MET-uHPLC- AB-101) = 1.85min, m/z (ES⁺) (M + H)⁺ 326 pentaene-4- carboxamide  8

355.37 10-methoxy-N-(5- methoxypyridin-3- yl)-7-thia-2,5,9-triazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4-carboxamide Tr(MET-uHPLC- AB-101) = 2.34 min, m/z (ES⁺) (M + H)⁺ 356  9

354.38 10-methoxy-N-(5- methoxypyridin-2- yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- Tr(METCR1600) = 4.72min, m/z (ES⁺) (M + H)⁺ 355 carboxamide 10

324.36 N-(5- methoxypyridin-3- yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamideTr(MET-uHPLC- AB-101) = 2.26 min, m/z (ES⁺) (M + H)⁺ 325 11

324.36 10-methoxy-N- (pyridin-4-yl)-7- thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- Tr(MET-uHPLC- AB-101)= 1.75 min, m/z (ES⁺) (M + H)⁺ 325 carboxamide 12

325.35 10-methoxy-N- (pyrazin-2-yl)-7- thia-2,5- diazatricyclo[6.4.0.0^(2,6)](dodeca- 1(12),3,5,8,10- pentaene-4- Tr(MET-uHPLC-AB-101) = 2.87 min, m/z (ES⁺) (M + H)⁺ 326 carboxamide

Method 5 Scheme for Method 5

Step 1, Method 5:10-Methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (95%, 60 mg, 0.23 mmol, described in Method 1) and6-amino-2-methyl-2,3-dihydropyridazin-3-one (60%, 48 mg, 0.23 mmol,described in PCT Int. Appl., WO 2011/015629) in pyridine (2 mL) werestirred at room temperature for 20 minutes.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97 mg, 0.51mmol) was added and the reaction stirred at room temperature undernitrogen overnight. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (97 mg, 0.51 mmol) was added and the reaction stirred atroom temperature under nitrogen for 2 days. The mixture was diluted withpyridine (2 mL) filtered, washed with methanol (2 mL), water (2 mL),methanol (2 mL) and heptane (2 mL). Purification by recrystallisationfrom 1:1 methanol:dimethylsulfoxide (5 mL) gave the title compound 24 mg(29% yield) as an off white powder.

Example 1: Method 5:10-Methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.04 (s, 1H), 8.99 (s, 1H), 8.08 (d, J=8.9 Hz,1H), 8.01 (d, J=9.8 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.9,2.2 Hz, 1H), 7.02 (d, J=9.8 Hz, 1H), 3.84 (s, 3H), 3.61 (s, 3H).Tr(METCR1600)=3.67 min, m/z (ES⁺) (M+H)⁺ 356.

The following example was prepared using Method 5 described above:

TABLE 5 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

355.37 10-methoxy-N-(1- methyl-6-oxo-1,6- dihydropyridazin-3-yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10-Tr(METCR 1600) = 3.67 min, m/z (ES⁺) (M + H)⁺ 356 pentaene-4-carboxamide

Method 6 Scheme for Method 6

Step 1, Method 6: Ethyl4-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate

A 1:4 mixture of ethyl4-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylateand ethyl5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate(356 mg, prepared by Method 19) was purified by FCC (silica, 0 to 40%dichloromethane in ethyl acetate) to give ethyl4-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate.¹H NMR (300 MHz, DMSO) 9.64 (d, J=5.4 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H),7.87 (d, J=9.0 Hz, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.27 (dd, J=9.0, 2.4 Hz,1H), 4.43 (q, J=6.9 Hz, 2H), 3.91 (s, 3H), 1.39 (t, J=6.9 Hz, 3H).

Step 2, Method 6:4-Methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid dihydrate

Ethyl4-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate(100 mg, 0.369 mmol) was suspended in 6 N aqueous hydrochloric acid andheated at 95° C. for 4 hours. The reaction mixture was cooled to roomtemperature. The resulting solid was collected by filtration,redissolved in saturated aqueous sodium bicarbonate solution (30 mL) andthe aqueous solution extracted with ethyl acetate (3×30 mL). The pH ofthe aqueous phase was adjusted to 1 with concentrated hydrochloric acid,and the resulting solid collected by filtration, washed with water (10mL) and dried under reduced pressure at room temperature. The solid wasthen suspended in water (3 mL), sonicated, isolated by filtration anddried in vacuo at room temperature for 18 hours to give the titlecompound. mp 256-257° C. (dec); ¹H NMR (500 MHz, DMSO) 13.89 (br s, 1H),9.63 (d, J=7.0 Hz, 1H), 8.03 (d, J=1.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H),7.61 (d, J=7.0 Hz, 1H), 7.27 (dd, J=9.0, 2.4 Hz, 1H), 3.90 (s, 3H).

Step 3, Method 6:4-Methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

4-Methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid dihydrate (25 mg, 0.1 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (42 mg, 0.11 mmol) and ethyldiisopropylamine(39 μl, 0.22 mmol) were dissolved in anhydrous N,N-dimethylformamide (1ml) and allowed to stir for 30 minutes. 5-Methoxypyridin-3-amine (13.mg, 0.11 mmol) was added and the reaction stirred at room temperaturefor 16 hours. Further portions of1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (10 mg, 0.03 mmol), ethyldiisopropylamine (9μl, 0.05 mmol) and 5-methoxypyridin-3-amine (5 mg, 0.04 mmol) were addedand the reaction stirred at room temperature for 3 hours. The reactionmixture was concentrated in vacuo and water and ethyl acetate wereadded. The mixture was filtered to give the title compound.

Example 1, Method 6:4-Methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

1H NMR (500 MHz, DMSO) 11.11 (s, 1H), 9.68 (d, J=6.9 Hz, 1H), 8.82 (s,1H), 8.11 (d, J=2.0 Hz, 1H), 8.03 (m, 2H), 7.87 (d, J=8.9 Hz, 1H), 7.73(d, J=6.9 Hz, 1H), 7.32-7.22 (m, 1H), 3.92 (s, 3H), 3.86 (s, 3H).Tr(MET-uHPLC-AB-101)=1.98 min, m/z (ES⁺) (M+H)⁺ 350.

The following example was prepared using Method 6 described above:

TABLE 6 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

349.35 4-methoxy-N-(5- methoxypyridin- 3-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)] trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET- uHPLC-AB- 101) = 1.98 min, m/z (ES⁺) (M + H)⁺ 350

Method 7 Scheme for Method 7

Step 1, Method 7:(3-{10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0²⁻⁶]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate

A suspension of10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide(100 mg, 0.308 mmol, prepared by Method 1) and 3-chloroperbenzoic acid(91 mg, 0.370 mmol) in chloroform (10 mL) was stirred for 2 days. Waterwas added and the solid collected by vacuum filtration. The solid waswashed with ethyl acetate and water and dried under suction. The solidwas suspended in methanol and transfered to a round bottomed flask. Thevolatiles were removed and the residue purified by neutral prep-HPLC togive the title compound.

Example 1, Method 7:(3-{10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate

¹H NMR (500 MHz, DMSO) 10.60 (s, 1H), 9.01-8.95 (m, 1H), 8.51-8.44 (m,1H), 8.11 (d, J=8.9 Hz, 1H), 7.91 (t, J=1.3 Hz, 1H), 7.81 (d, J=8.8 Hz,1H), 7.72 (d, J=2.5 Hz, 1H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 7.14-7.09 (m,1H), 3.85 (s, 3H). Tr(MET-uHPLC-AB-101)=1.92 min, m/z (ES⁺) (M+H)⁺ 341.

The following example was prepared using Method 7 described above:

TABLE 7 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

340.36 3-{10-methoxy-7- thia-2,5- diazatricyclo [6.4.0.0^(2,6)] dodeca-1(12),3,5,8,10- pentaene-4- Tr(MET-uHPLC- AB-101) = 2.13 min, m/z (ES⁺)(M + H)⁺ 341 amido}pyridin-1- ium-1-olate

Method 8 Scheme for Method 8

Step 1, Method 8:10-(2-Fluoroethoxy)-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide

10-Hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide(140 mg, 0.45 mmol, prepared by Method 2) was dissolved in toluene (3mL) and 2-fluoroethan-1-ol (38 mg, 0.59 mmol) was added, followed by(tributyl-lambda˜5˜-phosphanylidene)acetonitrile (154 μl, 0.59 mmol),and the reaction mixture stirred at ambient temperature under a nitrogenatmosphere for 16 hours. The reaction mixture was poured onto water andthe resulting emulsion filtered. The residual solid was triturated withethyl acetate and the solid dried under vacuum to give the titlecompound.

Example 1, Method 8:10-(2-Fluoroethoxy)-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.42 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.97 (s,1H), 8.33-8.24 (m, 2H), 8.12 (d, J=8.9 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H),7.37 (dd, J=8.2, 4.7 Hz, 1H), 7.24 (dd, J=8.9, 2.5 Hz, 1H), 4.91-4.68(m, 2H), 4.41-4.25 (m, 2H). Tr(MET-uHPLC-AB-101)=1.96 min, m/z (ES⁺)(M+H)⁺ 357.

The following examples were prepared using Method 8 described above:

TABLE 8 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

356.37 10-(2- fluoroethoxy)-N- (pyridin-3-yl)-7- thia-2,5- diazatricyclo[6.4.0.0^(2,6)] dodeca- Tr(MET- uHPLC-AB- 101) = 1.96 min, m/z (ES⁺)(M + H)⁺ 357 1(8),3,5,9,11- pentaene-4- carboxamide 2

461.50 10-[(5- methoxypyridin-2- yl)methoxy]-N-(5- methoxypyridin-3-yl)-7-thia-2,5- diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4- carboxamide Tr(MET- uHPLC-AB- 101) = 2.57 min, m/z (ES⁺)(M + H)⁺ 462

Method 9 Scheme for Method 9

Step 1, Method 9:N-(1-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(6-Oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide(90%, 30 mg, 0.09 mmol, prepared by Method 3) and Caesium carbonate (58mg, 0.18 mmol) were suspended in anhydrous N,N-dimethylformamide (3mIL), methyliodide (12 μl, 0.19 mmol) was added and the reaction stirredat 60° C. for 2 hours. The solvents were removed in vacuo and theresidue triturated with water (5 ml) and filtered. The residue waspurified by neutral HPLC to give the title compound.

Example 1, Method 9:N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 10.86 (s, 1H), 9.75 (d, J=7.0 Hz, 1H), 8.42 (d,J=8.2 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.86 (dd,J=9.7, 2.9 Hz, 1H), 7.72 (d, J=7.0 Hz, 1H), 7.66-7.57 (m, 1H), 7.58-7.47(m, 1H), 6.45 (d, J=9.7 Hz, 1H), 3.48 (s, 3H). Tr(MET-uHPLC-AB-101)=1.54min, m/z (ES⁺) (M+H)⁺ 320.

The following example was prepared using Method 9 described above:

TABLE 9 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

319.32 N-(1-methyl-6- oxo-1,6- dihydropyridin-3- yl)-1,8,10-triazatricyclo [7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- Tr(MET-uHPLC-AB- 101) = 1.54 min, m/z (ES⁺) (M + H)⁺ 320 hexaene-11-carboxamide

Method 10 Scheme for Method 10

Step 1, Method 10: Ethyl11-bromo-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate

6-Bromo-[1,3]thiazolo[5,4-b]pyridin-2-amine (0.1 g, 0.43 mmol) wasdissolved in N-methyl-2-pyrrolidone (1.5 mL) and ethyl3-bromo-2-oxopropanoate (64 μl, 0.43 mmol) added dropwise. The reactionwas stirred at room temperature for 1 hour then heated to 60° C.overnight. The reaction was cooled then water/ice added. The resultingprecipitate was isolated by vacuum filtration. The red solid was furtherdried in a vacuum oven to give the title compound. ¹H NMR (500 MHz,DMSO) 9.05 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 4.32(q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). Tr(MS10)=1.55 min, m/z (ES⁺)(M+H)⁺ 328, 329

Step 2, Method 10:11-Bromo-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid

Ethyl11-bromo-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(88%, 89 mg, 0.24 mmol) was suspended in methanol:toluene (1:1).Palladium(II) acetate (1:2) (2 mg, 0.002 mmol) and5-(di-tert-butylphosphanyl)-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole (2mg, 0.005 mmol) were added followed by caesium carbonate (117 mg, 0.36mmol) and the reaction stirred at 80° C. overnight. The reaction mixturewas allowed to cool, then concentrated in vacuo. Water and ethyl acetatewere added to form a slurry. 2 N Hydrochloric acid was added until pH 1.The precipitate was isolated by filtration to give the title compound.¹H NMR (500 MHz, DMSO) 12.85 (s, 1H), 8.96 (s, 1H), 8.93 (d, J=2.1 Hz,1H), 8.73 (d, J=2.1 Hz, 1H). Tr(METCR1410)=0.89 min, m/z (ES⁺) (M+H)⁺300, 302

Step 3, Method 110:11-Methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

11-Bromo-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (60 mg, 0.2 mmol) and 5-methoxypyridin-3-amine (25 mg, 0.2 mmol)were combined in pyridine (3 mL) and stirred for 10 minutes.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46 mg,0.24 mmol) was added and the solution stirred overnight at roomtemperature. Water was added then the solution concentrated to dryness.The crude solid was slurried with water and isolated by filtration togive the title compound.

Example 1, Method 10:11-Bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0²⁻⁶]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.51 (s, 1H), 9.00 (s, 1H), 8.98 (d, J=2.0 Hz,1H), 8.73 (m, 2H), 8.05 (d, J=2.6 Hz, 1H), 7.98 (appt t, J=2.3 Hz, 1H),3.83 (s, 3H). Tr(MET-uHPLC-AB-101)=2.4 min, m/z (ES⁺) (M+H)⁺ 404, 406.

The following example was prepared using Method 10 described above:

TABLE 10 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

404.24 11-bromo-N-(5- methoxypyridin- 3-yl)-7-thia-2,5,9- triazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamide Tr(MET-uHPLC-AB-101) = 2.4 min, m/z (ES⁺) (M + H)⁺ 404, 406

Method 11 Scheme for Method 11

Step 1, Method 11: Ethyl10-hydroxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate

Ethyl 3-bromo-2-oxopropanoate (4.2 mL, 33.1 mmol) was added dropwise toa stirred solution of 2-amino-1,3-benzothiazol-6-ol (5 g, 30.1 mmol) inN,N-dimethylacetamide (100 mL) at room temperature. The reaction mixturewas heated to 100° C. for 3 hours. The reaction was cooled to roomtemperature and water (200 mL) added. A precipitate formed and themixture was filtered. The collected solid was dried under vacuum to givethe title compound. ¹H NMR (500 MHz, DMSO) 10.03 (s, 1H), 8.89 (s, 1H),7.95 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.8, 2.3 Hz,1H), 4.28 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H). Tr(METCR1410)=0.91min, m/z (ES⁺) (M+H)⁺ 263.

Step 2, Method 11: Ethyl10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate

Ethyl10-hydroxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(500 mg, 1.91 mmol) and prop-2-en-1-ol (178 μL, 2.48 mmol) weresuspended in anhydrous toluene (5 mL), cyanomethylenetributylphosphorane(650 μL, 2.48 mmol) was added and the reaction heated to 100° C. in asealed tube for 2 hours. The reaction mixture was cooled to roomtemperature and the solvents removed in vacuo. The residue wastriturated with 1:1 diethyl ether:heptane to give the title compound. ¹HNMR (500 MHz, DMSO) 8.96 (s, 1H), 8.08 (d, J=8.9 Hz, 1H), 7.70 (d, J=2.5Hz, 1H), 7.18 (dd, J=8.9, 2.5 Hz, 1H), 6.07 (ddt, J=17.2, 10.6, 5.3 Hz,1H), 5.43 (dq, J=17.3, 1.6 Hz, 1H), 5.29 (dd, J=10.5, 1.5 Hz, 1H),4.60-4.68 (m, 2H), 4.29 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).Tr(METCR1410)=1.13 min, m/z (ES⁺) (M+H)⁺ 303.

Step 3, Method 11:10-(Prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid

Ethyl10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(95%, 445 mg, 1.4 mmol) was suspended in 1:1 tetrahydrofuran/water (8mL), lithium hydroxide (67 mg, 2.8 mmol) added and the reaction wasstirred at room temperature for 2 days. The reaction mixture wasacidified to approximately pH 4 by the addition of 2 M hydrochloricacid, a precipitate formed which was collected by filtration to give thetitle compound. ¹H NMR (500 MHz, DMSO) 12.60 (s, 1H), 8.88 (s, 1H), 8.05(d, J=8.9 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.17 (dd, J=8.9, 2.5 Hz, 1H),6.07 (ddt, J=17.2, 10.6, 5.3 Hz, 1H), 5.44 (dd, J=17.3, 1.7 Hz, 1H),5.29 (dd, J=10.5, 1.5 Hz, 1H), 4.64 (d, J=5.3 Hz, 2H).Tr(METCR1410)=0.97 min, m/z (ES⁺) (M+H)⁺ 275.

Step 4, Method 11:N-(1-Methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-(Prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (275 mg, 1 mmol), 6-amino-2-methyl-2,3-dihydropyridazin-3-one (138mg, 1.1 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (419 mg, 1.1 mmol) and ethyldiisopropylamine(0.52 ml, 3.01 mmol) were dissolved in N,N-dimethylformamide (10 mL) andthe reaction mixture stirred at room temperature for 45 minutes. Thereaction mixture was then heated to 60° C. for two days. After this timethe reaction mixture was cooled to room temperature, water added and theresultant precipitate collected by filtration and triturated withmethanol to give the title compound.

Example 1, Method 11:N-(1-Methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.08 (s, 1H), 9.00 (s, 1H), 8.08 (d, J=8.9 Hz,1H), 8.01 (d, J=9.8 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.20 (dd, J=8.9,2.5 Hz, 1H), 7.03 (d, J=9.8 Hz, 1H), 6.16-5.97 (m, 1H), 5.44 (dd,J=17.3, 1.6 Hz, 1H), 5.30 (dd, J=10.5, 1.4 Hz, 1H), 4.65 (d, J=5.3 Hz,2H), 3.61 (s, 3H). Tr(MET-uHPLC-AB-101)=2.97 min, m/z (ES⁺) (M+H)⁺ 382.

The following example was prepared using Method 11 described above:

TABLE 11 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

381.41 N-(1-methyl-6- oxo-1,6- dihydropyridazin- 3-yl)-10- (prop-2-en-1-yloxy)-7-thia- 2,5- Tr(MET-uHPLC- AB-101) = 2.97 min, m/z (ES⁺) (M + H)⁺382 diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4-carboxamide

Method 12 Scheme for Method 12

Step 1, Method 12:10-Methoxy-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carbaldehyde

Part 1

A suspension of 6-methoxy-1H-1,3-benzodiazole-2-thiol (5.00 g, 27.74mmol), bromopropanedial (4.19 g, 27.74 mmol), and potassium carbonate(3.83 g, 27.74 mmol) in N,N-dimethylformamide was heated to 80° C. for 4hours, cooled, the solvents removed in vacuo and the residue dilutedwith water (100 mL). The pH was adjusted to about 5 with 1 Mhydrochloric acid, at which point a solid formed. The solid was isolatedby filtration and rinsed with water to afford the crude intermediatedi-aldehyde, which was used directly in the next part with no furtherpurification.

Part 2

The solids from part 1 were dissolved in aceticacid:N,N-dimethylformamide (20 mL, 3:1) and heated to 120° C. for 40minutes. The reaction mixture was cooled and the solvents removed invacuo. The residue was diluted with water (100 mL) and the resultingsolids filtered off to give a regioisomeric mixture of aldehydes (3:2 infavour of the desired isomer—as determined by NMR). The crude mixturewas filtered through a pad of silica, then recrystallised twice frommethanol-ethyl acetate to give the title compound: ¹H NMR (250 MHz,DMSO) 9.97 (s, 1H), 9.43 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.3Hz, 1H), 6.98 (dd, J=8.9, 2.4 Hz, 1H), 3.83 (s, 3H).).Tr(METCR1410)=1.05 min, m/z (ES⁺) (M+H)⁺ 231.

Step 2, Method 12:10-Methoxy-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxylicacid

To a suspension of10-methoxy-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carbaldehyde(180 mg, 0.77 mmol) in water-tertiary butanol (1:3, 8 mL) was added2-methylbut-2-ene (163 mg, 2.32 mmol), sodium dihydrogen phosphate (372mg, 3.1 mmol) and sodium chlorite (80%, 263 mg, 2.32 mmol). Theresulting orange suspension was stirred overnight at room temperature.The bulk of the solvents were removed in vacuo, the residue dissolved inwater-acetonitrile and purified by acid phase preparative HPLC to affordthe title compound. ¹H NMR (250 MHz, DMSO) 9.20 (s, 1H), 8.00 (d, J=8.9Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.9, 2.4 Hz, 1H), 3.82 (s,3H). Tr(METCR1410)=0.88 min, m/z (ES⁺) (M+H)⁺ 246.

Step 3, Method 12:10-Methoxy-N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide

To a solution of10-methoxy-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxylicacid (32 mg, 0.13 mmol) and 5-methoxypyridin-3-amine (18 mg, 0.14 mmol)in pyridine (2 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (32 mg,0.17 mmol). The reaction was stirred at room temperature for 45 minutesbefore water was slowly added (5 mL) and the resulting slurry stirredfor a further 15 minutes. The resulting solid was filtered off and driedto give the title compound.

Example 1, Method 12:10-Methoxy-N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.75 (s, 1H), 9.20 (s, 1H), 8.50 (d, J=2.0 Hz,1H), 8.10 (d, J=2.6 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.80 (appt t, J=2.3Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 6.97 (dd, J=8.8, 2.4 Hz, 1H), 3.85 (s,3H), 3.84 (s, 3H). Tr(METCR1600)=3.9 min, m/z (ES⁺) (M+H)⁺ 355.

The following examples were prepared using Method 12 described above:

TABLE 12 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

354.38 10-methoxy-N-(5- methoxypyridin-3- yl)-5-thia-2,7- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,6,8,10- pentaene-4- carboxamideTr(METCR1600) = 3.9 min, m/z (ES⁺) (M + H)⁺ 355 2

355.37 10-methoxy-N-(1- methyl-6-oxo-1,6- dihydropyridazin-3-yl)-5-thia-2,7- diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,6,8,10-Tr(MET- uHPLC-AB- 101) = 2.06 min, m/z (ES⁺) (M + H)⁺ 356 pentaene-4-carboxamide 3

339.37 10-methoxy-N-(2- methylpyrimidin- 5-yl)-5-thia-2,7- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,6,9,11- pentaene-4- Tr(MET- uHPLC-AB- 101)= 2.15 min, m/z (ES⁺) (M + H)⁺ 340.1 carboxamide

Method 13 Scheme for Method 13

Step 1, Method 13:N-(2-Hydroxypyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(2-Methoxypyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide(154 mg, 0.48 mmol, prepared by Method 3) was suspended indichloromethane (15 mL) and 1 M tribromoborane (6.7 mL) added dropwise.The reaction mixture was stirred at room temperature under a nitrogenatmosphere for 4.5 days. The reaction mixture was quenched with water(20 mL) and the mixture concentrated in vacuo. The residue was suspendedin tetrahydrofuran (40 mL) and the pH increased to 7 by the addition ofsaturated aqueous sodium hydrogen carbonate solution. The mixture wasfiltered to give the title compound. ¹H NMR (500 MHz, DMSO) 10.86 (s,1H), 9.75 (d, J=7.0 Hz, 1H), 8.60 (s, 2H), 8.42 (d, J=8.2 Hz, 1H), 7.95(d, J=8.2 Hz, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.63 (appt t, J=7.7 Hz, 1H),7.52 (appt t, J=7.7 Hz, 1H). Tr(METCR1410)=0.77 min, m/z (ES⁺) (M+H)⁺307.

Step 2, Method 13:N-(1-Methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(2-Hydroxypyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide(50 mg, 0.16 mmol) and potassium carbonate (85 mg, 0.62 mmol) weresuspended in NN-dimethylformamide (2 mL). Methyl iodide (200 μL, 10%solution in N,N-dimethylformamide) was added and the reaction mixturestirred at room temperature for 23 hours. The solvent was removed invacuo and the residue triturated with water. Purification by FCC(silica, 0-100% 9:1 dichloromethane:methanol in dichloromethane) gavethe title compound.

Example 1, Method 13:N-(1-Methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 11.09 (s, 1H), 9.78 (d, J=7.0 Hz, 1H), 8.92 (d,J=3.4 Hz, 1H), 8.74 (d, J=3.4 Hz, 1H), 8.43 (d, J=8.2 Hz, 1H), 7.96 (d,J=8.2 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.68-7.61 (m, 1H), 7.58-7.49 (m,1H), 3.50 (s, 3H). Tr(MET-uHPLC-AB-101)=1.4 min, m/z (ES⁺) (M+H)⁺ 321.

The following example was prepared using Method 13 described above:

TABLE 13 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

320.31 N-(1-methyl-2- oxo-1,2- dihydropyrimidin- 5-yl)-1,8,10-triazatricyclo [7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11-carboxamide Tr(MET-uHPLC- AB-101) = 1.4 min, m/z (ES⁺) (M + H)⁺ 321

Method 14 Scheme for Method 14

Step 1, Method 14:11-Methoxy-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid

Ethyl11-bromo-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(0.1 g, 0.31 mmol, prepared by Method 1),di-tert-butyl({3,6-dimethoxy-2-[2,4,6-tris(propan-2-yl)phenyl]phenyl})phosphane(3 mg, 0.01 mmol) and caesium carbonate (40 μL, 0.46 mmol) were added toa round bottomed flask and sealed. The flask was evacuated via a syringeneedle to the vacuum line and purged with nitrogen. This process wasrepeated three times. Methanol (0.3 mL) was then added. In a separateflask was addedmethanesulfonato(2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(Strem Chemicals, Inc., cat number 46-0325) (5 mg, 0.01 mmol). The flaskwas sealed and evacuated via a syringe needle to the vacuum line andpurged with nitrogen. This was repeated three times. Dioxane (2 mL) wasadded to the flask and the mixture stirred and degassed with nitrogenfor 1 minute. This was transferred to the first flask via a cannulaneedle and heated to 50° C. for 24 hours. An additional portion ofligand was added to the reaction in tetrahydrofuran (2 mL) and heatingcontinued at 50° C. overnight. An additional portion of ligand was addedto the reaction in tetrahydrofuran (2 mL) and heating continued at 50°C. for 5 hours. The reaction was reduced to dryness then loaded directlyonto silica and purified by FCC (0-100% ethyl acetate in heptane) togive the title compound. ¹H NMR (500 MHz, DMSO) 9.08 (s, 1H), 8.36-8.37(m, 2H), 3.95 (s, 3H), 3.85 (s, 3H). Tr(METCR1410)=0.91 min, m/z (ES⁺)(M+1)⁺ 264, 76%.

Step 2, Method 14:11-Methoxy-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid

Methyl11-methoxy-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(76%, 23 mg, 0.07 mmol) was suspended in tetrahydrofuran:water (4 mL:4mL) and lithium hydroxide (8 mg, 0.33 mmol) added in one portion. Thereaction was stirred at room temperature. The reaction was heated to 50°C. overnight. Potassium hydroxide (20 mg, 0.36 mmol) was added andstirring continued at 50° C. for 1 hour. The solution was allowed tocool and the tetrahydrofuran removed. The aqueous layer was slowlyacidified to pH 1. Half the volume of water was removed under reducedpressure. The resultant precipitate was isolated by filtration and driedto give the title compound. ¹H NMR (500 MHz, DMSO) 12.79 (br s, 1H),9.01-8.86 (m, 1H), 8.34-8.35 (m, 2H), 3.95 (s, 3H). Tr(METCR1410)=0.86min, m/z (ES⁺) (M+H)⁺ 250, 77%.

Step 3, Method 14:11-Methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

11-Methoxy-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (77%, 17 mg, 0.05 mmol) and 5-methoxypyridin-3-amine (7 mg, 0.05mmol) were combined in pyridine (1 mL) and stirred for 10 minutes.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10 mg,0.06 mmol) was added in one portion and the reaction stirred overnight.The reaction was diluted with water then the solid isolated byfiltration. The crude was purified byneutral prep-HPLC to give the titlecompound.

Example 1, Method 14:11-Methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.49 (s, 1H), 9.02 (s, 1H), 8.73 (d, J=2.0 Hz,1H), 8.40 (d, J=2.7 Hz, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.05 (d, J=2.7 Hz,1H), 7.99 (appt t, J=2.3 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H).Tr(MET-uHPLC-AB-101)=2.16 min, m/z (ES⁺) (M+H)⁺ 356.

The following examples were prepared using Method 14 described above:

TABLE 14 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

355.37 11-methoxy-N- (5- methoxypyridin- 3-yl)-7-thia- 2,5,9-triazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4-Tr(MET-uHPLC- AB-101) = 2.16 min, m/z (ES⁺) (M + H)⁺ 356 carboxamide 2

356.36 11-methoxy-N- (1-methyl-6- oxo-1,6- dihydropyridazin-3-yl)-7-thia- 2,5,9- triazatricyclo Tr(MET-uHPLC- AB-101) = 2.29 min,m/z (ES⁺) (M + H)⁺ 357 [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4- carboxamide

Method 15 Scheme for Method 15

Step 1, Method 15: tert-ButylN-[(3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-amido}phenyl)methyl]-N-methylcarbamate

10-Methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxylicacid (50 mg, 0.2 mmol, prepared by Method 1) and tert-butylN-[(3-aminophenyl)methyl]-N-methylcarbamate (52 mg, 0.22 mmol) weredissolved in pyridine and stirred at room temperature for 5 minutes.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (42.47 mg,0.22 mmol) was added and stirring continued at room temperature for 5hours. Water (10 mL) was added to the reaction mixture and a precipitateformed which was collected by filtration and dried under vacuum to givethe title compound. ¹H NMR (500 MHz, DMSO) 10.09 (s, 1H), 8.92 (s, 1H),8.11 (d, J=8.9 Hz, 1H), 7.83 (d, J=50.1 Hz, 1H), 7.69-7.74 (m, 2H), 7.30(appt t, J=7.8 Hz, 1H), 7.18 (dd, J=8.9, 2.5 Hz, 1H), 6.93 (d, J=6.9 Hz,1H), 4.37 (s, 2H), 3.85 (s, 3H), 2.78 (s, 3H), 1.42 (s, 9H).Tr(METCR1410)=1.31 min, m/z (ES⁺) (M+H)⁺ 467.

Step 2, Method 15:10-Methoxy-N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide

Tert-butylN-[(3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-amido}phenyl)methyl]-N-methylcarbamate(59 mg, 0.15 mmol) was suspended in dichloromethane (2 mL),trifluoroacetic acid (1 mL) was added and the reaction mixture stirredat room temperature for 3 days. The reaction mixture was diluted withdichloromethane (25 mL) and water (25 mL). The layers were separated andthe organic layer washed with saturated aqueous sodium carbonatesolution, dried over magnesium sulphate, filtered and concentrated invacuo to give the title compound.

Example 1, Method 15:10-Methoxy-N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.01 (s, 1H), 8.91 (s, 1H), 8.11 (d, J=8.9 Hz,1H), 7.88 (s, 1H), 7.74-7.66 (m, 2H), 7.29 (appt t, J=7.8 Hz, 1H), 7.18(dd, J=8.9, 2.5 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.85 (s, 3H), 3.71 (s,2H), 2.33 (s, 3H). Tr(MET-uHPLC-AB-101)=1.91 min, m/z (ES⁺) (M+H)⁺ 367.

The following example was prepared using Method 15 described above:

TABLE 15 Mol. LCMS Ex. Structure Weight IUPAC Name data 1

366.44 10-methoxy-N-{3- [(methylamino) methyl]phenyl}-7- thia-2,5-diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11- pentaene-4- Tr(MET-uHPLC- AB-101) = 1.91 min, m/z (ES⁺) (M + H)⁺ 367 carboxamide

Method 16 Scheme for Method 16

Step 1, Method 16: Ethyl10-bromo-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate

Ethyl 3-bromo-2-oxopropanoate (1.2 ml, 9.6 mmol) was added dropwise to astirred solution of 6-bromo-1,3-benzothiazol-2-amine (2 g, 8.73 mmol) inN,N-dimethylacetamide (50 mL) at room temperature. The reaction mixturewas heated to 100° C. for 18 hours. The reaction mixture was cooled toroom temperature and water was added and the mixture filtered. Thecollected solid was dried under vacuum for 2 hours to give the titlecompound. ¹H NMR (500 MHz, DMSO) 9.04 (s, 1H), 8.36 (d, J=1.9 Hz, 1H),8.13 (d, J=8.6 Hz, 1H), 7.77 (dd, J=8.6, 2.0 Hz, 1H), 4.30 (q, J=7.1 Hz,2H), 1.31 (t, J=7.1 Hz, 3H); Tr(METCR1410)=1.14 min, m/z (ES⁺) (M+H)⁺325/327, 81%.

Step 2, Method 16:10-Bromo-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid

Ethyl10-bromo-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate(81%, 2.03 g, 5.06 mmol) was suspended in 1:1 tetrahydrofuran/water (50mL), lithium hydroxide (242 mg, 10.11 mmol) was added and the reactionmixture stirred at room temperature for 18 hours. The reaction mixturewas acidifed with 2 M hydrochloric acid until a precipitate formed whichwas collected by filtration. The collected solid was dried under vacuumto give the title compound. ¹H NMR (500 MHz, DMSO) 8.97 (s, 1H), 8.36(d, J=1.9 Hz, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.77 (dd, J=8.6, 2.0 Hz, 1H);Tr(METCR1410)=0.98 min, m/z (ES⁺) (M+H)⁺ 297/299.

Step 3, Method 16:10-Bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-Bromo-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxylicacid (1.5 g, 5.05 mmol) and 5-methoxypyridin-3-amine (752 mg, 6.06 mmol)were suspended in pyridine (20 mL) and the mixture stirred at roomtemperature for 10 minutes.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.16 g,6.06 mmol) was added and the reaction mixture stirred at roomtemperature for 4 days. Water (15 mL) was added and the precipitatecollected by filtration and dried under vacuum for 3 hours to give thetitle compound. ¹H NMR (500 MHz, DMSO) 10.43 (s, 1H), 9.03 (s, 1H), 8.71(d, J=2.0 Hz, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 8.04(d, J=2.6 Hz, 1H), 7.97 (appt t, J=2.3 Hz, 1H), 7.80 (dd, J=8.6, 2.0 Hz,1H), 3.83 (s, 3H); Tr(METCR1410)=1.11 min, m/z (ES⁺) (M+H)⁺ 403/405.

Step 4, Method 16:10-[(Dimethylamino)methyl]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-Bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide(350 mg, 0.87 mmol) in dioxane (18 mL) was added to a solution ofpotassium Rdimethylamino)methylltrifluoroborate (186 mg, 1.13 mmol) inwater (4 mL), followed by the addition of palladium(II) acetate (39 mg,0.17 mmol), SPhos (2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 143mg, 0.35 mmol) and potassium phosphate (1474 mg, 6.94 mmol). Theresulting mixture was stirred at 115° C. for 22 hours under a flow ofnitrogen. The solvents were removed in vacuo. Purification by FCC(silica, 0-100% 9:1 dichloromethane/methanol in dichloromethane) gavethe title compound.

Example 1, Method 16:10-[(Dimethylamino)methyl]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

¹H NMR (500 MHz, DMSO) 10.43 (s, 1H), 9.00 (s, 1H), 8.73 (d, J=2.0 Hz,1H), 8.15 (d, J=8.3 Hz, 1H), 8.05 (d, J=2.6 Hz, 1H), 8.00 (s, 1H), 7.99(appt t, J=2.3 Hz, 1H), 7.51 (dd, J=8.3, 1.3 Hz, 1H), 3.84 (s, 3H), 3.52(s, 2H), 2.19 (s, 6H). Tr(METCR1600)=4.13 min, m/z (ES⁺) (M+H)⁺ 382.

The following examples were prepared using Method 16 described above:

TABLE 16 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

381.45 10- [(dimethylamino) methyl]-N-(5- methoxypyridin-3-yl)-7-thia-2,5- diazatricyclo [6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4- carboxamide Tr(METCR1600) = 4.13 min, m/z (ES⁺) (M + H)⁺ 3822

400.46 N-(5- methoxypyridin-3- yl)-10-phenyl-7- thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10- pentaene-4- carboxamide Tr(MET-uHPLC-AB-101) = 3.34 min, m/z (ES⁺) (M + H)⁺ 401

Method 17 Scheme for Method 17

Step 1, Method 17:11-(Trichloromethyl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene

1H-1,3-Benzodiazol-2-amine (4 g, 30 mmol) and(3E)-1,1,1-trichloro-4-ethoxybut-3-en-2-one (6.53 g, 30 mmol) weresuspended in anhydrous toluene (60 mL). Triethylamine (4.2 mL, 30 mmol)was added and the reaction was heated to 120° C. for 2.5 hours. Thereaction mixture was cooled to room temperature and the solvents removedin vacuo. Water was added, and the residue sonicated and filtered. Thecrude material was dissolved in dichloromethane (500 mL) and washed with2 M sodium hydroxide (300 mL), the organic layer was concentrated invacuo to give the title compound. ¹H NMR (500 MHz, DMSO) 9.78 (d, J=7.3Hz, 1H), 8.42 (d, J=8.2 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.76 (d, J=7.2Hz, 1H), 7.63 (appt t, J=7.7 Hz, 1H), 7.56-7.50 (m, 1H).Tr(METCR1410)=1.09 min, m/z (ES⁺) (M+H)⁺ 286/288, 80%.

Step 2, Method 17: Ethyl1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate

11-(Trichloromethyl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene(5.43 g, 19 mmol) was suspended in sulphuric acid (45 mL) and heated to140° C. for 1 hour. The reaction mixture was cooled to room temperatureand ethanol (250 mL) was added. The reaction was heated to 80° C.overnight. The reaction mixture was cooled to room temperature andethanol (100 mL) was added. The reaction mixture was stirred at 80° C.overnight. The reaction mixture was cooled to room temperature, theethanol removed in vacuo and the acidic residue was basified by additionof solid sodium hydrogen carbonate. The basic layer was diluted withwater (500 mL) and extracted with dichloromethane (3×1 L). The combinedorganics were dried over anhydrous magnesium sulphate, filtered and thefiltrate concentrated in vacuo to give the title compound. ¹H NMR (500MHz, DMSO) 9.74 (d, J=7.0 Hz, 1H), 8.43 (d, J=8.2 Hz, 1H), 7.97 (d,J=8.3 Hz, 1H), 7.67-7.62 (m, 2H), 7.55-7.50 (m, 1H), 4.45 (q, J=7.1 Hz,2H), 1.41 (t, J=7.1 Hz, 3H). Tr(METCR1410)=0.87 min, m/z (ES⁺) (M+H)⁺242.

Step 3, Method 17: Ethyl4-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylateand ethyl5-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate

Ethyl1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate(3.99 g, 17.0 mmol) was dissolved in dichloromethane (200 mL),N-bromosuccinimide (7.35 g, 41.3 mmol) added and the reaction stirred atroom temperature overnight. The reaction mixture was diluted in furtherdichloromethane (300 ml) and N-bromosuccinimide (7.35 g, 41.3 mmol)added. The reaction was stirred at room temperature for 3 hours. Thereaction mixture was retreated with N-bromosuccinimide (14.7 g, 82.59mmol) and the reaction mixture stirred at room temperature for 5 days.The reaction mixture was diluted with dichloromethane (1 L) and theorganic was washed with 1 M sodium hydroxide (800 mL). The organics weredried over magnesium sulfate, filtered and the filtrate concentrated invacuo to give the title compound mixture. ¹H NMR (500 MHz, DMSO) 9.70(d, J=7.0 Hz, 1H), 8.78 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.75(dd, J=8.8, 2.0 Hz, 1H), 7.67 (d, J=7.0 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H),1.41-1.38 (m, 3H). Tr(METCR1410)=1.03 min, m/z (ES⁺) (M+H)⁺ 320/322,90%.

Step 4, Method 17:4-Bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid and5-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid

A mixture of ethyl4-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylateand ethyl5-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylate(1000 mg, 3.12 mmol) was suspended in methanol (50 mL), potassiumcarbonate (432 mg, 3.12 mmol) added and the reaction stirred at roomtemperature for 2 days. The reaction mixture was retreated withpotassium carbonate (432 mg, 3.12 mmol) and a few drops of water added.The reaction mixture was stirred at room temperature overnight. Thesolvents were removed in vacuo, the residue acidified with 2 Mhydrochloric acid (15 mL) and filtered. The precipitate was concentratedfrom methanol (30 mL) to afford the title compound mixture. ¹H NMR (500MHz, DMSO) 9.77 (d, J=7.0 Hz, 1H), 8.83 (d, J=1.8 Hz, 1H), 7.92 (d,J=8.8 Hz, 1H), 7.80 (dd, J=8.8, 1.9 Hz, 1H), 7.78 (d, J=7.0 Hz, 1H).Tr(METCR1410)=0.80 min, m/z (ES⁺) (M+H)⁺ 292/294.

Step 5, Method 17:4-Bromo-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamideand5-bromo-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

A mixture of4-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid and5-bromo-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid (285 mg, 0.98 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (408 mg, 1.07 mmol) andethyldiisopropylamine (0.4 mL, 2.15 mmol) were dissolved in anhydrousN,N-dimethylformamide (5 mL) and stirred at room temperature for 30minutes. 5-Methoxypyridin-3-amine (133 mg, 1.07 mmol) was added and thereaction stirred at room temperature for 16 hours. The reaction mixturewas retreated with1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (408 mg, 1.07 mmol), ethyldiisopropylamine(0.4 mL, 2.15 mmol) and N,N-dimethylformamide (2 mL) and stirred at roomtemperature for 72 hours. Water was added to the reaction mixture and itwas filtered to give the title compound mixture. ¹H NMR (500 MHz, DMSO)11.19 (s, 1H), 9.81-9.73 (m, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.6Hz, 1H), 8.04-8.00 (m, 1H), 7.97-7.90 (m, 2H), 7.84-7.78 (m, 1H),7.77-7.74 (m, 1H), 3.86 (s, 3H). Tr(METCR1410)=1.02 min, m/z (ES⁺)(M+H)⁺ 398/400, 85%.

Step 6, Method 17:N,5-Bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamideandN,4-Bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

A mixture of4-bromo-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamideand5-bromo-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide(85%, 246 mg, 0.53 mmol), (5-methoxypyridin-3-yl)boronic acid (88 mg,0.58 mmol), RuPhos (2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl,49 mg, 0.11 mmol) and tripotassium phosphate (223 mg, 1.05 mmol) indioxane/water (2 mL/1 mL) was purged with nitrogen gas and palladium(II)acetate (12 mg, 0.05 mmol) added. The reaction was irradiated undermicrowave conditions at 140° C. for 3 hours. The reaction mixture wasdiluted with water and filtered. The precipitate was dissolved indimethylsulfoxide and a few drops of water were added to initiateprecipitation. The mixture was filtered and dried. The resulting solidwas purified by acidic HPLC to giveN,5-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamideandN,4-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide.The isomers were separate according to methods known in the art.

Example 1, Method 17:N,5-Bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 11.21 (s, 1H), 9.84 (d, J=7.0 Hz, 1H), 8.83 (d,J=2.0 Hz, 1H), 8.65 (d, J=1.8 Hz, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.35 (d,J=1.3 Hz, 1H), 8.33 (d, J=2.7 Hz, 1H), 8.12 (d, J=2.6 Hz, 1H), 8.06-8.04(m, 1H), 7.94 (dd, J=8.6, 1.7 Hz, 1H), 7.84-7.80 (m, 2H), 3.96 (s, 3H),3.87 (s, 3H). Tr(METCR1603)=3.61 min, m/z (ES⁺) (M+H)⁺ 427, 92%.

Example 2, Method 17:N,4-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 9.83 (d, J=7.0 Hz, 1H), 8.94 (s, 1H), 8.83 (d,J=2.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.7 Hz, 1H), 8.13 (d,J=2.6 Hz, 1H), 8.05 (m, 3H), 7.85 (d, J=7.0 Hz, 1H), 7.80 (m, 1H), 3.97(s, 3H), 3.87 (s, 3H).

The following examples were prepared using Method 17 described above:

TABLE 17 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

426.44 N,5-bis(5- methoxypyridin- 3-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(METCR 1603) = 3.61 min, m/z (ES⁺) (M + H)⁺ 427 2

426.44 N,4-bis(5- methoxypyridin- 3-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(METCR 1603) = 3.63 min, m/z (ES⁺) (M + H)⁺ 427

Method 18 Scheme for Method 18

Step 1, Method 18:N-[5-(2-Methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(5-Hydroxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide(35 mg, 0.11 mmol, prepared by Method 3) was suspended inN,N-dimethylformamide (2 mL) and sodium hydride (3 mg, 0.11 mmol) addedin one portion. The reaction was stirred for 15 minutes then1-chloro-2-methoxyethane added and the reaction stirred at 50° C. for 3days. Water (0.5 mL) was added and the reaction concentrated. The crudeproduct was purified by high pH preparative HPLC to give the titlecompound.

Example 1, Method 18:N-[5-(2-Methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 11.18 (s, 1H), 9.80 (d, J=7.0 Hz, 1H), 8.83 (s,1H), 8.45 (d, J=8.2 Hz, 1H), 8.13 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.98(d, J=8.3 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.66 (appt t, J=7.7 Hz, 1H),7.54 (appt t, J=7.7 Hz, 1H), 4.25-4.17 (m, 2H), 3.75-3.69 (m, 2H), 3.34(s, 3H). Tr(MET-uHPLC-AB-101)=1.89 min, m/z (ES⁺) (M+H)⁺ 364.

The following example was prepared using Method 18 described above:

TABLE 18 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

363.38 N-[5-(2- methoxyethoxy) pyridin-3-yl]- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET- uHPLC-AB-101) = 1.89 min, m/z (ES⁺) (M + H)⁺ 364

Method 19 Scheme for Method 19

Step 1, Method 19: (E)-Ethyl 4-ethoxy-2-oxobut-3-enoate

Pyridine (8 mL, 7.8 g, 98.9 mmol) was added drop-wise over 2 minutes toa solution of ethyl 2-chloro-2-oxoacetate (11 mL, 98.5 mmol) indichloromethane (135 mL) cooled in an ice-water bath. Ethyl vinyl ether(9.5 mL, 7.2 g, 99.2 mmol) was then added dropwise over 5 minutes, theresulting mixture was stirred with ice bath cooling for 30 minutes andwarmed to room temperature. Water (100 mL) was added, the layers wereseparated and the organic layer washed with saturated sodium bicarbonatesolution (100 mL) and brine (100 mL), dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound. ¹H NMR(500 MHz, CDCl₃) 7.87 (d, J=12.5 Hz, 1H), 6.19 (d, J=12.5 Hz, 1H), 4.33(q, J=7.5 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 1.29-1.42 (m, 6H).

Step 2, Method 19: Ethyl8-methoxybenzo[4,5]imidazo[1,2-a]pyrimidine-2-carboxylate

A mixture of 5-methoxy-1H-benzo[d]imidazol-2-amine (5.6 g, 34.3 mmol),(E)-ethyl 4-ethoxy-2-oxobut-3-enoate (5.9 g, 34.5 mmol) andtriethylamine (4.8 mL, 3.5 g, 34.7 mmol) in toluene (115 mL) was heatedat 80° C. for 18 hours. The mixture was cooled to room temperature. Thevolatiles were removed in vacuo and the residue obtained was adsorbedonto silica gel and purified by FCC (silica, dichloromethane to 95:5dichloromethane/methanol) to give a 66:34 mixture of 8-methoxy and7-methoxy regioisomers. The product was suspended in acetonitrile (550mL), heated at 100° C. for 2.5 hours and then cooled to room temperatureand left overnight. The solid product was isolated by filtration anddried to give an 81:19 mixture of 8-methoxy:7-methoxy. Hot triturationfrom acetonitrile was repeated once with 450 mL of solvent and threetimes with 35-40 mL of solvent to give the title compound. ¹H NMR (500MHz, DMSO) 9.65 (d, J=6.5 Hz, 1H), 8.31 (d, J=9.0 Hz, 1H), 7.63 (d,J=7.0 Hz, 1H), 7.42, (d, J=2.0 Hz, 1H), 7.13 (dd, J=9.0, 2.5 Hz, 1H),4.43 (q, J=7.5 Hz, 2H), 3.90 (s, 3H), 1.40 (t, J=7.5 Hz, 3H).

Step 3, Method 19:5-Methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2,4,6,8,10,12-hexaene-11-carboxylicacid

A suspension of ethyl8-methoxybenzo[4,5]imidazo[1,2-a]pyrimidine-2-carboxylate (3.1 g, 11.4mmol) in 6 N hydrochloric acid (140 mL) was heated at 95° C. for 4hours. After this time the mixture was allowed to cool to roomtemperature. The resulting yellow precipitate was collected byfiltration, dissolved in saturated sodium bicarbonate solution (100 mL)and the solution extracted with ethyl acetate (8×200 mL). The pH of theaqueous layer was adjusted to 1 by addition of 1 N hydrochloric acid andthe precipitated product collected by filtration and dried at reducedpressure to give the title compound. mp 270-273° C., dec; ¹H NMR (500MHz, DMSO) 13.85 (br s, 1H), 9.63 (d, J=7.0 Hz, 1H), 8.30 (d, J=9.0 Hz,1H), 7.62 (d, J=7.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.12 (dd, J=9.0,2.5 Hz, 1H), 3.90 (s, 3H).

Step 4, Method 19:5-Methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

5-Methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2,4,6,8,10,12-hexaene-11-carboxylicacid (95%, 50 mg, 0.2 mmol) and pyridin-3-amine (21 mg, 0.21 mmol) weresuspended in anhydrous N,N-dimethylformamide (3 ml).Ethyldiisopropylamine (0.1 ml, 0.58 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (90 mg, 0.24 mmol) were added and thereaction stirred at room temperature for 16 hours. The reaction mixturewas concentrated in vacuo and water (20 mL) added. The mixture wasfiltered through glass fibre filter paper and the precipitate purifiedby FCC (silica, 0-7% methanol in dichloromethane) to give the titlecompound.

Example 1, Method 19:5-Methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 11.17 (s, 1H), 9.71 (d, J=6.9 Hz, 1H), 9.13 (d,J=2.3 Hz, 1H), 8.39-8.34 (m, 2H), 8.32 (d, J=9.0 Hz, 1H), 7.77 (d, J=6.9Hz, 1H), 7.45 (dd, J=8.3, 4.7 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.14 (dd,J=9.0, 2.4 Hz, 1H), 3.91 (s, 3H). Tr(METCR1600)=3.33 min, m/z (ES⁺)(M+H)⁺ 320.

The following examples were prepared using Method 19 described above:

TABLE 19 Mol. Ex. Structure Weight IUPAC Name LCMS data 1

319.32 5-methoxy-N- (pyridin-3-yl)- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET- uHPLC-AB-101) = 1.48 min, m/z (ES⁺) (M + H)⁺ 320 2

350.34 5-methoxy-N-(1- methyl-6-oxo-1,6- dihydropyridazin- 3-yl)-1,8,10-triazatricyclo [7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11-Tr(METCR1600) = 3.39 min, m/z (ES⁺) (M + H)⁺ 351 carboxamide 3

348.37 5-methoxy-11-{1- methyl- 1H,4H,5H,6H- pyrrolo[3,4-c] pyrazole-5-carbonyl}-1,8,10- triazatricyclo [7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12- hexaene Tr(MET- uHPLC-AB-101) = 1.64 min, m/z (ES⁺)(M + H)⁺ 349 4

349.35 5-methoxy-N-(5- methoxypyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET- uHPLC-AB-101) = 1.91 min, m/z (ES⁺) (M + H)⁺   350.1 5

385.39 N-[6-(1H- imidazol-1- yl)pyridin-3-yl]-5- methoxy-1,8,10-triazatricyclo [7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11-carboxamide Tr(MET- uHPLC-AB-101) = 1.57 min, m/z (ES⁺) (M + H)⁺ 386 6

344.33 N-(3- cyanopyridin-4- yl)-5-methoxy- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(MET- uHPLC-AB-101) = 2.3 min, m/z (ES⁺) (M + H)⁺ 7

349.35 5-methoxy-N-(6- methoxypyridin-3- yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene-11- carboxamideTr(METCR1600) = 3.65 min, m/z (ES⁺) (M + H)⁺ 350

Method 20 Scheme for Method 20

Step 1, Method 20: 2-(2-Methoxyethoxy)-5-nitropyridine

2-Methoxyethanol (5.22 mL, 66.23 mmol) was treated with sodium hydride(0.57 g, 14.2 mmol) at room temperature in several portions over 10minutes. After stirring at room temperature for 30 minutes2-chloro-5-nitropyridine (1.5 g, 9.5 mmol) was added in two portions andstirred for 20 minutes. The reaction was poured onto water, filtered andthe solid dried in a vacuum oven overnight to give the title compound.¹H NMR (500 MHz, Chloroform) 9.06 (d, J=2.7 Hz, 1H), 8.35 (dd, J=9.1,2.8 Hz, 1H), 6.89 (d, J=9.1 Hz, 1H), 4.63-4.55 (m, 2H), 3.80-3.73 (m,2H), 3.44 (s, 3H). Tr(METCR1410)=0.94 min, m/z (ES⁺) (M+H)⁺ 199.

Step 2, Method 20: 6-(2-Methoxyethoxy)pyridin-3-amine

To a suspension of 2-(2-methoxyethoxy)-5-nitropyridine (500 mg, 2.52mmol) in ethanol (20 mL) was added Palladium on charcoal (10% metal byweight) (134 mg, 0.126 mmol). The reaction vessel was flushed withnitrogen 3 times before placing under a hydrogen atmosphere (3×vacuum-hydrogen cycles) and stirred at room temperature for 6 hours. Themixture was filtered through a pad of Celite, washed with methanol andthe solvent removed in vacuo to give the title compound, which was usedin the next step with no further purification. Tr(METCR1410)=0.16 min,m/z (ES⁺) (M+H)⁺ 169.

Step 3, Method 20:N-[6-(2-Methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

To a solution of1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxylicacid (100 mg, 0.328 mmol, prepared by Method 3) in N,N-dimethylformamide(4 ml) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (187 mg, 0.345 mmol) andN,N-diisopropylethylamine (76 μL, 0.493 mmol) at room temperature andstirred for one hour. 6-(2-Methoxyethoxy)pyridin-3-amine (66 mg, 0.394mmol) was added and the reaction was stirred for 24 hours. The reactionmixture was concentrated in vacuo and the residue dissolved indimethylsulfoxide and purified by preparative HPLC (high pH). Theproduct containing fractions contained a solid which was isolated byfiltration, washed with acetonitrile and dried in a vacuum oven to givethe title compound.

Example 1, Method 20:N-[6-(2-Methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide

¹H NMR (500 MHz, DMSO) 11.06 (s, 1H), 9.77 (d, J=7.0 Hz, 1H), 8.69 (d,J=2.7 Hz, 1H), 8.43 (d, J=8.2 Hz, 1H), 8.22 (dd, J=8.9, 2.7 Hz, 1H),7.96 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.67-7.60 (m, 1H),7.55-7.49 (m, 1H), 6.89 (d, J=8.9 Hz, 1H), 4.38 (dd, J=5.4, 4.0 Hz, 2H),3.68-3.65 (m, 2H), 3.31 (s, 3H). Tr(MET-uHPLC-AB-101)=2.20 min, m/z(ES⁺) (M+H)⁺ 364.

The following example was prepared using Method 20 described above:

TABLE 20 Mol. IUPAC Ex. Structure Weight Name LCMS data 1

363.37 N-[6-(2- methoxyethoxy) pyridin-3- yl]-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12- hexaene- 11- carbboxamideTr(MET- uHPLC-AB- 101) = 2.20 min, m/z (ES⁺) (M + H)⁺ 364

Synthesis of10-[¹¹C]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide

10-[¹¹C]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamidewas synthesized from Compound 2 of Method 2 via O-methylation, using[¹¹C]methyl triflate (obtained from cyclotron-produced[¹¹C]methane) asan alkylating agent in the presence of base according to the method ofChitneni, S. K. et al.: Synthesis and biological evaluation ofcarbon-11-labeled acyclic and furo[2,3-d]pyrimidine derivatives ofbicyclic nucleoside analogues (BCNAs) for structurebrain uptakerelationship study of BCNA tracers, Journal of Labelled Compounds andRadiopharmaceuticals 2008, 51, 159-166. The incorporation rate was >90%and the radiochemical purity was >99%. The labeled product was purifiedon semi-preparative HPLC column (Ascentis RP-Amide C18) usingacetonitrile/aq. triethylamine (0.1%) as eluent. The product was thenconcentrated using solid-phase extraction procedure (on Waters tC18 Vac1 cc SPE cartridge) and formulated in sterile saline (0.9% NaCl)with >10% ethanol. The radiochemical purity of the product was analyzedon an HPLC system using Ascentis RP-Amide C18 analytical column andacetonitrile/aq. triethylamine (0.1%) as eluent, with sequential UVabsorbance and radioactivity detectors. The radiochemical purity of theformulated product was determined to be >99%.

The following compounds can be prepared according to the syntheticmethods similar to those described above.

TABLE 21 Structure IUPAC Name

N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-[6-(1H-imidazol-1-yl)pyridin- 3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-[2-(dimethylamino)ethyl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-(2-methoxyethyl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4- carboxamide

N-(6-oxo-1,6-dihydropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-{[3,3′-bipyridine]-6-yl}-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-(6-oxo-1,6-dihydropyridazin- 3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-(pyridin-3-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide

5-methoxy-N-[6- (methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide

5-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

5-methoxy-N-(6-oxo-1,6- dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

5-methoxy-N-(pyridin-3-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide

N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide

5-methoxy-N-(2- methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(5,6-dimethoxypyridin-3-yl)- 5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene

N-[6-(1H-imidazol-1-yl)pyridin- 3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

5-methoxy-N-(6-oxo-1,6- dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(3-cyano-2-methoxypyridin- 4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

10-methoxy-N-(5- methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

N-(pyridin-4-yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4- carboxamide

N-(pyrazin-2-yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4- carboxamide

3-{7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4- amido}pyridin-1-ium-1-olate

5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(5-methoxypyridin-3-yl)-5- thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,6,8,10-pentaene-4-carboxamide

N-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,6,8,10-pentaene-4-carboxamide

N-(2-methylpyrimidin-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,6,9,11-pentaene-4-carboxamide

5-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)- 1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-{3- [(methylamino)methyl]phenyl}- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

5-methoxy-N-[5-(2- methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(pyridin-3-yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4- carboxamide

N-(6-methoxypyridin-3-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

N-[(pyridin-3-yl)methyl]-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

N-methyl-N-(pyridin-3-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

N-(1-benzofuran-5-yl)-7-thia- 2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4- carboxamide

N-(1-methyl-1H-pyrazol-4-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

N-(6-fluoropyridin-3-yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4- carboxamide

N-[6-(methylcarbamoyl)pyridin- 3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

4-{1H,2H,3H- pyrrolo[2,3-c]pyridine-1- carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene

4-{1-methyl-1H,4H,5H,6H- pyrrolo[3,4-c]pyrazole-5- carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene

N-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide

5-methoxy-N-[6-(2- methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(2,6-dimethoxypyridin-3-yl)- 5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(6-fluoro-5-methoxypyridin- 3-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-[6-(2-fluoroethoxy)pyridin-3- yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-[5-(2-fluoroethoxy)pyridin-3- yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(2,6-dimethoxypyridin-3-yl)- 1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(6-fluoro-5-methoxypyridin- 3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-[6-(2-fluoroethoxy)pyridin-3- yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-[5-(2-fluoroethoxy)pyridin-3- yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-[1-(2-fluoroethyl)-6-oxo-1,6- dihydropyridazin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide

N-(2-methoxypyrimidin-5-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

10-methoxy-N-(2- methoxypyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide

BIOLOGY EXAMPLES Example A Q46 Radioligand Binding Assay

For radioligand binding assays (RBA) GST-Q46 protein was generated basedon a previous publication (Scherzinger et al. Cell, Vol. 90, 549-558,Aug. 8, 1997). For experiments 33 μM GST-Q46 was incubated with 150μg/mL thrombin in assay buffer (150 mM NaCl, 50 mM Tris pH 8.0) and 2 mMCaCl₂ for 16 hours at 37° C. Aggregated Q46 was pelleted bycentrifugation for 5 minutes at 13,000 rpm in a bench top centrifuge andre-dissolved in the same volume of assay buffer. Test compounds wereprepared by titration in DMSO at 11 concentrations from 33 μM to 1 nM.For the RBA, Q46 protein aggregates and test compounds werepre-incubated in assay buffer for 20 minutes at room temperature, in 140μL/well in a 96-well plate (pp, round bottom). Then, ligand was added in10 μL/well and incubated for 60 minutes at 37° C. Final assayconcentrations were 1 μM to 30 pM test compound, 5 μM Q46 protein(equivalent monomer concentration) and 10 nM ligand [³H₃]MK-3328(Harrision et al., ACS Med. Chem. Lett., 2 (2011), pp 498-502). Sampleswere transferred onto GF/B filter plates and washed 2× with 200 μL PBSusing a Filtermate Harvester. After drying filter plates for 1 hour at37° C., the back of the plates was sealed with foil and 30 μl/wellscintillation fluid (Packard MicroScint 40) was added, incubated forincubated for 15 minutes in the dark and counted in a TopCount reader.For analysis, replicate data from independent assay plates werenormalized towards 0% and 100% inhibition using control wells of vehicle(0% inhibition) and 3 μM unlabelled MK-3328 (100% inhibition). IC₅₀values were determined with a sigmoidal inhibition model with fourvariables (top, bottom, slope, IC₅₀) in a global fit using thenormalized replicate data.

RBA IC₅₀ activity summary <100 nM+++, 100-500 nM++, >500 nM+

TABLE 22 Ac- tiv- Structure IUPAC Name ity

10-methoxy-N-(pyridin-3-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(6- methoxypyridin-3-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(pyridin-3- ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +

10-methoxy-N-methyl-N- (pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide ++

N-(1-benzofuran-5-yl)-10- methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-hydroxy-N-(6- methoxypyridin-3-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N-(6-methoxypyridin-3-yl)- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide +++

N-(6-fluoropyridin-3-yl)- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide +++

10-hydroxy-N-(pyridin-3-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(5- methoxypyridin-3-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(1-methyl-1H- pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide ++

N-(6-fluoropyridin-3-yl)-10- methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(pyridin-3-yl)- 7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(5- methoxypyridin-3-yl)-7-thia- 2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-[6- (methylcarbamoyl)pyridin-3- yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-4-{1H,2H,3H- pyrrolo[2,3-c]pyridine-1- carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene +

10-methoxy-N-(6- methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-4-{1-methyl- 1H,4H,5H,6H- pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene +++

10-methoxy-N-(1-methyl-6- oxo-1,6-dihydropyridazin-3- yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(2- methylpyrimidin-5-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N-[6-(1H-imidazol-1- yl)pyridin-3-yl]-10-methoxy- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(pyrimidin-5- yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N-[2-(dimethylamino)ethyl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide ++

10-methoxy-N-(2- methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide ++

10-methoxy-N-(6-oxo-1,6- dihydropyridin-3-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-[5-(pyridin-3- yl)pyridin-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(6-oxo-1,6- dihydropyridazin-3-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

5-methoxy-N-(pyridin-3-yl)- 1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-[6- (methylcarbamoyl)pyridin-3- yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-(5-methoxypyridin-3-yl)- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide +++

N-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-(6-oxo-1,6-dihydropyridin- 3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-(pyridin-3-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide +

N-(3-cyanopyridin-4-yl)-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide +++

N-(2-methoxypyridin-4-yl)- 1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11- carboxamide +++

N-(5,6-dimethoxypyridin-3- yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

5-methoxy-N-(1-methyl-6- oxo-1,6-dihydropyridazin- 3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

5-methoxy-11-{1-methyl- 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10- triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene +++

4-methoxy-N-(5- methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

5-methoxy-N-(5- methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-[6-(1H-imidazol-1- yl)pyridin-3-yl]-5-methoxy- 1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-(3-cyanopyridin-4-yl)-5- methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-(6-oxo-1,6- dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-(3-cyano-2- methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

5-methoxy-N-(6- methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

10-methoxy-N-(5- methoxypyridin-2-yl)-7-thia- 2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N-(5-methoxypyridin-3-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(pyridin-4-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(pyrazin-2-yl)- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

3-{10-methoxy-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4- amido}pyridin-1-ium-1-olate ++

10-(2-fluoroethoxy)-N- (pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide +++

N-({10-methoxy-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaen-4- yl}methyl)pyridin-3-amine +

10-[(5-methoxypyridin-2- yl)methoxy]-N-(5- methoxypyridin-3-yl)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide ++

11-bromo-N-(5- methoxypyridin-3-yl)-7-thia- 2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5- diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4- carboxamide +++

10-methoxy-N-(5- methoxypyridin-3-yl)-5-thia- 2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,6,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(1-methyl-6- oxo-1,6-dihydropyridazin-3- yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,6,8,10-pentaene-4-carboxamide +++

10-methoxy-N-(2- methylpyrimidin-5-yl)-5-thia- 2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,6,9,11-pentaene-4-carboxamide +++

N-(1-methyl-2-oxo-1,2- dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

11-methoxy-N-(5- methoxypyridin-3-yl)-7-thia- 2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

11-methoxy-N-(1-methyl-6- oxo-1,6-dihydropyridazin-3- yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

10-methoxy-N-{3-[(methyl- amino)methyl]phenyl}- 7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),3,5,9,11-pentaene-4-carboxamide +++

10-[(dimethylamino)methyl]- N-(5-methoxypyridin-3-yl)-7- thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide ++

N-(5-methoxypyridin-3-yl)- 10-phenyl-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca- 1(12),3,5,8,10-pentaene-4-carboxamide +++

N,5-bis(5-methoxypyridin-3- yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N,4-bis(5-methoxypyridin-3- yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-[5-(2- methoxyethoxy)pyridin-3-yl]- 1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

N-[ 6-(2- methoxyethoxy)pyridin-3-yl]- 1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),3,5,8,10,12-hexaene-11-carboxamide +++

Example B Binding of tritiated Compound 1 of Method 1(10-[³H]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide)to Aβ Aggregates

Generation of tritiated compound 1, Method 1, for autoradiographystudies was achieved by treating phenolic Compound 2 of Method 2 withtritiated methyl nosylate and a suitable base in N,N-dimethylformamidePurification by HPLC gave the tritiated compound in high radiochemicalpurity.

Brains were extracted from 12 month old heterozygous APP/PS1 animals (J.Neurochemistry 2009, 108, 1177-1186) and quickly frozen on dry ice insmall weigh boats, wrapped with tin foil and stored in zip-lock bags at−80° C. for sectioning. Using a Leica CM3050S cryostat, 20 μm thicksections were generated representing the hippocampus (Bregma−1.34/−3.80) and the cortex/striatum (Bregma 1.54/−0.94). Sections weremounted on poly-Lysine coated slides and instantly dried with a slidewarmer.

10-[³H]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamidebinding was determined in brain sections of a 12 month old APP/PS1 mouseand a WT littermate. The Aβ aggregate-specific radioligand, ³H-PiB, wasused as a positive control. One slide was used to determine totalbinding and one slide was used to determine non-specific binding at eachradioligand concentration. Non-specific binding was determined for eachradioligand in the presence of 1 μM of respective, cold ligandequivalent.

After washing, brain sections were dipped in ice-cold deionized water,and then dried under a stream of cool air. Slides were loaded into thecassette of a Beta-imager 2000, and the images of the brain sectionswere acquired for 48 hours in zoom mode setting.

Quantification and Analysis: Signal intensity (cpm/mm²) was measured foreach brain section using Beta Vision+software. Specific (displaceable)binding, expressed in cpm/mm², was defined by the difference betweentotal and non-specific binding and calculated as follows:(Total non-specific)/Total×100%.

Statistical Analysis: Statistical significance determined by 2way ANOVAwith Tukey's multiple comparisons test (*p<0.05).

Results: FIG. 1 shows that Aβ aggregates are visible in the 12-month oldheterozygous APP/PS1 mouse brain after incubation with 1 nM10-[³H]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide(FIG. 1A), as compared with a wild-type littermate (FIG. 1B). Binding ofthe positive control compound ³H-PiB to 18-month old heterozygousAPP/PS1 mouse brain is shown in FIG. 2. mHTT aggregates are visible inthe 10 week old R6/2 mouse brain after incubation with 0.5 nM7-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]imidazo[2,1-b]thiazole-2-carboxamide(as shown in FIG. 4A) as compared with a wild-type littermate (as shownin FIG. 4B).

Example C In Vivo Imaging with [¹¹C]-Compound 1 of Method 1(10-[¹¹C]-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide)in a Knock-In Model of Huntington's Disease

¹¹C-labeled Compound 1 of Method 1 was evaluated for its ability topenetrate the central nervous system of mice following systemicadministration, and its binding to the cerebellum, striatum,hippocampus, and cortex was quantitated. Three groups of animals werecompared: wild-type, and mice that were heterozygous or homozygous forthe zQ175 knock-in allele. (Menalled L. B. et al. Comprehensivebehavioral and molecular characterization of a new knock-in mouse modelof Huntington's disease: zQ175. PloS One 2012, 7, e49838). Forty-eightnine months old animals (16 WT, 16 heterozygous and 16 homozygous zQ175)were obtained from The Jackson Laboratory, USA. The animals were housedat the animal department of Karolinska University Hospital in atemperature (±21° C.) and humidity (±40%) controlled environment on a 12hour light/dark cycle (lights on 7:00 AM) with access to food and waterad libitum. Animals were allowed at least one week to habituate to theanimal department before the start of the imaging sessions. Allexperiments were conducted during the light phase of the cycle.

Animals were anesthetized with inhalation of isoflurane (4-5% isofluranein oxygen). After induction of anesthesia, the isoflurane concentrationwas lowered to 1.5-2% in 50/50 air/oxygen and the animals werepositioned in the scanner in a designated mouse bed. A cannula wasinserted in the tail vein through which the radioligand wasadministered. A 63-minute dynamic PET scan was initiated immediatelyupon intravenous injection of the radioligand. Upon completion of theimaging sessions, each animal was returned to its cage.

Image and Statistical Analysis

The acquired list mode data, was reconstructed into 25 timeframes (63minute scan=4×10 s, 4×20 s, 4×60 s, 7×180 s, 6×360 s). The imagereconstruction was made with a fully 3-dimensional maximum-likelihoodexpectation maximization algorithm (MLEM) with 20 iterations, withoutscatter and attenuation correction. The reconstructed dynamic PET imageswere co-registered to an inbuilt mouse MRI template available in PMOD,which also incorporates volumes of interest (VOI's) sets (PMODTechnologies Ltd., Zurich, Switzerland). With the help of these VOIsets, decay corrected time activity curves (TAC) were generated. Theregional brain uptake values were expressed as percent standard uptakevalue (% SUV), which normalizes for injected radioactivity and bodyweight. In addition, the area under the curve (AUC) was calculated. Theselected regions of interest (ROI) were: cortex, hippocampus, striatumand cerebellum.

The average % SUV and AUC values for the ¹¹C-labeled Compound 1 ofMethod 1 in the four brain regions, for the three groups of mice, areshown in Table 23. Increased binding of the radioligand, relative towild type, was observed in all four brain regions in mice which werehomozygous for the zQ175 allele. FIG. 3 presents the AUC values for thethree groups of animals in the four regions of the brain.

TABLE 23 Average % SUV and AUC values of ¹¹C-labeled Compound 1 ofMethod 1 in the cortex, hippocampus, striatum and cerebellum of WT, hetzQ175 and hom zQ175 animals. Each value is expressed as Mean ± SD % SUVAUC WT Het Hom WT Het Hom (n = 7) (n = 6) (n = 8) (n = 7) (n = 6) (n =8) Cortex 67.1 ± 5.7 73.4 ± 5.1 93.1 ± 9.6 2036 ± 131 2236 ± 116 3542 ±397 Hippocampus 73.3 ± 6.5 82.0 ± 6.3 107.1 ± 10.8 1965 ± 101 2212 ± 1203570 ± 274 Striatum 71.9 ± 6.7 82.7 ± 7.0 107.6 ± 9.6  1906 ± 97  2243 ±146 3597 ± 231 Cerebellum 74.1 ± 7.1 80.5 ± 6.5  92.3 ± 11.3 2043 ± 96 2219 ± 135 3024 ± 221

Various modifications, additions, substitutions, and variations to theillustrative examples set forth herein will be apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

The invention claimed is:
 1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2;n is 1 or 2; J is C(═O) or —CH₂—; X is S or N; Y is CH or N; Z is CH orN; W is N; for each occurrence, R₁ is independently chosen from halo,lower alkoxy, hydroxy, aryl, heteroaryl, or cycloalkoxy, wherein thelower alkoxy, cycloalkoxy, aryl, or heteroaryl are each optionallysubstituted with one, two, or three groups independently selected fromlower alkoxy, alkenyl, —NR₄R₅, halo, or heteroaryl optionallysubstituted with one to three lower alkoxy; or R₁ is lower alkyloptionally substituted with —NR₄R₅; R₂ is hydrogen or lower alkyl; andR₃ is pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl,1H-pyrazol-4-yl, 6-oxo-1,6-dihydropyridazin-3-yl, pyrimidin-5-yl,6-oxo-1,6-dihydropyridin-3-yl, pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl,or 2-oxo-1,2-dihydropyrimidin-5-yl, each of which is optionallysubstituted with one, two, or three groups independently chosen fromhydroxy, lower alkoxy optionally substituted with lower alkoxy, loweralkyl optionally substituted with halo, halo, heteroaryl,—(CH₂)_(t)NR₄R₅, cyano, and —C(O)—NR₄R₅; t is 0, 1, or 2; each R₄ isindependently chosen from hydrogen or lower alkyl; each R₅ isindependently chosen from hydrogen or lower alkyl; or R₄ and R₅ takentogether with the nitrogen to which they are bound form aheterocycloalkyl ring, optionally substituted with one, two, or threegroups independently chosen from hydroxy, lower alkoxy, lower alkyl,halo, or —C(O)—NR₆R₇; each R₆ is independently chosen from hydrogen orlower alkyl; and each R₇ is independently chosen from hydrogen or loweralkyl.
 2. A compound of claim 1, wherein the compound is of Formula1(a):


3. A compound of claim 1, wherein Y is CH.
 4. A compound of claim 1,wherein Y is N.
 5. A compound of claim 1, wherein Z is CH.
 6. A compoundof claim 1, wherein Z is N.
 7. A compound of claim 1, wherein thecompound is of Formula II(a):


8. A compound of claim 1, wherein the compound is Formula II(b):


9. A compound of claim 1, wherein X is S.
 10. A compound of claim 1,wherein X is N.
 11. A compound of claim 1, wherein R₂ is hydrogen.
 12. Acompound of claim 1, wherein R₂ is methyl.
 13. A compound of claim 1,wherein R₃ is chosen from pyridin-3-yl, 5-methoxypyridin-3-yl,6-methoxypyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,6-(methylcarbamoyl)pyridin-3-yl, 1-benzofuran-5-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 1-methyl-1H-pyrazol-4-yl,2-methylpyrimidin-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl,6-oxo-1,6-dihydropyridin-3-yl, 5-(pyridin-3-yl)pyridin-2-yl,6-(methylcarbamoyl)pyridin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl,2-methoxypyridin-4-yl, 5,6-dimethoxypyridin-3-yl, 3-cyanopyridin-4-yl,3-cyano-2-methoxypyridin-4-yl, 5-methoxypyridin-2-yl, pyridin-4-yl,pyrazin-2-yl, 1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl,5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl. 14.A compound of claim 1, wherein n is
 1. 15. A compound of claim 1,wherein n is
 2. 16. A compound of claim 1, wherein m is
 1. 17. Acompound of claim 1, wherein m is
 2. 18. A compound of claim 16,wherein, for each occurrence, R₁ is independently chosen from halo,lower alkoxy, hydroxy, aryl, or heteroaryl, wherein the lower alkoxy,aryl, or heteroaryl are each optionally substituted with one to twogroups independently selected from lower alkoxy, alkenyl, —NR₄R₅, halo,or heteroaryl optionally substituted with one to two lower alkoxy.
 19. Acompound of claim 16, wherein, for each occurrence, R₁ is independentlychosen from bromo, methoxy, 2-fluoroethoxy, prop-2-en-1-yloxy,(dimethylamino)methyl, phenyl, 5-methoxypyridin-3-yl,(5-methoxypyridin-2-yl)methoxy, or hydroxy.
 20. A compound of claim 1,wherein m is
 0. 21. A compound of claim 1, wherein each R₄ isindependently chosen from hydrogen or C₁₋₃alkyl.
 22. A compound of claim1, wherein each R₅ is independently chosen from hydrogen or C₁₋₃alkyl.23. A compound of claim 1, wherein each R₆ is independently chosen fromhydrogen or C₁₋₃alkyl.
 24. A compound of claim 1, wherein each R₇ isindependently chosen from hydrogen or C₁₋₃alkyl.
 25. A compound, or apharmaceutically acceptable salt thereof, selected from:10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(6-fluoropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(6-fluoropyridin-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(pyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;10-methoxy-N-(6-methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene;10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(pyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-[2-(dimethylamino)ethyl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(2-methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(6-oxo-1,6-dihydropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-[5-(pyridin-3-yl)pyridin-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;5-methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-[6-(methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(3-cyanopyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(5,6-dimethoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;5-methoxy-11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene;4-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;5-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-(3-cyano-2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;5-methoxy-N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;10-methoxy-N-(5-methoxypyridin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(pyridin-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(pyrazin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate;10-(2-fluoroethoxy)-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;N-({10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaen-4-yl}methyl)pyridin-3-amine;10-[(5-methoxypyridin-2-yl)methoxy]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;11-bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;10-methoxy-N-(2-methylpyrimidin-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,6,9,11-pentaene-4-carboxamide;N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;11-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;11-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;10-methoxy-N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;10-[(dimethylamino)methyl]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N-(5-methoxypyridin-3-yl)-10-phenyl-7-thia-2,5-diazatricyclo[6.4.0.0^(2,6)]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;N,5-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N,4-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;N-[5-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;andN-[6-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0^(2,7)]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide.26. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adjuvant, excipient, or diluent.
 27. A pharmaceuticalcomposition comprising a compound of claim 25, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable adjuvant,excipient, or diluent.